Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof

ABSTRACT

The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof: 
                         
which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which is associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/665,789, filed on May 2, 2018. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates generally to compounds and pharmaceuticalcompositions useful as ASK-1 inhibitors. Specifically, the presentinvention relates to compounds useful as inhibitors of ASK-1 and methodsfor their preparation and use.

BACKGROUND OF THE INVENTION

Apoptosis signal-regulating kinase 1 (ASK-1) is a member of themitogen-activated protein kinase kinase kinase (MAPKKK, MAP3K) family,which when activated phosphorylates downstream MAP kinase kinases(MAPKK, MAP2K), which in turn activate MAP kinases (MAPK). MAPKs elicita response by phosphorylating cellular substrates, thus regulating theactivity of transcription factors that ultimately control geneexpression. Specifically ASK-1, also known as MAPKKK5, phosphorylatesMAPKK4/MAPKK7 or MAPKK3/MAPKK6, which subsequently phosphorylates andactivates the c-Jun N-terminal protein kinase (NK) and p38 MAPKs,respectively (H. Ichijo, et al., Cell Comm. Signal 2009, 7, 1-10; K.Takeda, et al., Annu. Rev. Pharmacol. Toxicol. 2008, 48, 199-225; H.Nagai, et al., J. Biochem. Mol. Biol. 2007, 40, 1-6). Activation of theJNK and p38 pathways triggers a downstream stress response such asapoptosis, inflammation, or differentiation (H. Ichijo, et al., Science1997, 275, 90-94; K. Takeda, et al., J. Biol. Chem. 2000, 275,9805-9813; K. Tobiume, et al., EMBO Rep. 2001, 2, 222-228; K. Sayama etal., J. Biol. Chem. 2001, 276, 999-1004).

The activity of ASK-1 is regulated by thioredoxin (Trx), which binds tothe N-terminal end of ASK-1 (M. Saitoh, et al., EMBO J. 1998, 17,2596-2606). ASK-1 is activated succeeding autophosphorylation at Thr838in response to environmental stimuli including oxidative stress,lipopolysaccharides (LPS), reactive oxygen species (ROS), endoplasmicreticulum (ER) stress, an increase in cellular calcium ionconcentrations, Fas ligand, and various cytokines such as tumor necrosisfactor (TNF) (H. Nishitoh, et al., Genes Dev. 2002, 16, 1345-1355; K.Takeda, et al., EMBO Rep. 2004, 5, 161-166; A. Matsuzawa, et al., Nat.Immunol. 2005, 6, 587-592).

ASK-1 has been associated with autoimmune disorders, neurodegenerativedisorders, inflammatory diseases, chronic kidney disease, cardiovasculardisease, metabolic disorders, and acute and chronic liver diseases (R.Hayakawa, et al., Proc. Jpn. Acad., Ser. B 2012, 88, 434-453).

More specifically, ASK-1 has been associated with hepatic steatosis,including non-alcoholic fatty liver disease (NAFLD) and non-alcoholicsteatohepatitis (NASH). In a mouse model, high fat diets have causedinduction of hepatic steatosis, ultimately causing fat accumulation andfatty acid oxidation. This led to the generation of ROS which causedhepatocyte dysfunction and death (S. K. Mantena, et al., Free Radic.Biol. Med. 2008, 44, 1259-1272; S. K. Mantena, et al., Biochem. J. 2009,417, 183-193). Moreover, TNF was shown to be critical for apoptosis ofhepatocytes through the ASK-1-JNK pathway, and TNF deficient mice showedreduced hepatic steatosis and fibrosis (W. Zhang, et al., Biochem.Biophys. Res. Commun. 2010, 391, 1731-1736).

Small molecule compounds which act as ASK-1 inhibitors have beendisclosed in the following publications: WO 2008/016131, WO 2009/027283,WO 2009/0318425, WO 2009/123986, US 2009/0318425, WO 2011/041293, WO2011/097079, US 2011/0009410, G. P. Volynets, et al., J. Med. Chem.2011, 54, 2680-2686, WO 2012/003387, WO 2012/011548, WO 2012/080735, Y.Terao, et al., Bioorg. Med. Chem. Lett. 2012, 22, 7326-7329, WO2013/112741, G. P. Volynets, et al., Eur. J. Med. Chem. 2013, 16,104-115, US 2014/0018370, WO 2014/100541, WO 2015/095059, WO2016/049069, WO 2016/049070, WO 2018/090869, WO 2018/133865, WO2018/133866, WO 2018/148204, WO 2018/149284, WO 2018/151830,WO/2018/157856, WO 2018/157857, WO 2018/160406, WO 2018/169742, WO2018/183122, WO 2018/187506, WO 2018/209354, WO 2018/218042, WO2018/218044, WO 2018/218051, WO 2018/233553, US 2019/0062310, WO2019/070742, WO 2019/050794, WO 2019/051265, and WO 2019/034096.

There is a need for the development of ASK-1 inhibitors for thetreatment and prevention of disease.

SUMMARY OF THE INVENTION

The present invention relates to compounds and pharmaceuticalcompositions useful as ASK-1 inhibitors. Specifically, the presentinvention relates to compounds useful as inhibitors of ASK-1 and methodsfor their preparation and use. In addition, the present inventionincludes the process for the preparation of the said compounds.

In its principal aspect, the present invention provides a compound ofFormula (I), or a pharmaceutically acceptable salt or ester thereof:

wherein

is optionally substituted aryl or optionally substituted heteroarylcontaining 1, 2 or 3 heteroatoms selected from N, O and S, provided that

is not

In certain embodiments,

is selected from:

is

is

R¹ and R² are each independently selected from the group consisting of:1) Hydrogen;2) Optionally substituted —C₁-C₈ alkyl;3) Optionally substituted —C₂-C₈ alkenyl;4) Optionally substituted —C₂-C₈ alkynyl;5) Optionally substituted —C₃-C₈ cycloalkyl;6) Optionally substituted aryl;7) Optionally substituted arylalkyl;8) Optionally substituted 3- to 8-membered heterocycloalkyl;9) Optionally substituted heteroaryl; and10) Optionally substituted heteroarylalkyl;X is N or C—R³;R³ is selected from the group consisting of:1) Hydrogen;2) Halogen;3) Optionally substituted —C₁-C₈ alkyl; and4) Optionally substituted —C₁-C₈ alkoxyl;R⁴ is selected from the group consisting of:1) Hydrogen;2) Halogen;3) Optionally substituted —C₁-C₈ alkyl;4) Optionally substituted —C₂-C₈ alkenyl;5) Optionally substituted —C₂-C₈ alkynyl;6) Optionally substituted —C₃-C₈ cycloalkyl;7) Optionally substituted aryl;8) Optionally substituted arylalkyl;9) Optionally substituted 3- to 8-membered heterocycloalkyl;10) Optionally substituted heteroaryl;11) Optionally substituted heteroarylalkyl; and12) —N(R⁵)(R⁶);wherein R⁵ and R⁶ are independently selected from the group consistingof hydrogen, —C₁-C₈ alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, all of which are optionally substituted with 1-3substituents selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, —CN, alkoxy, —CF₃, aryl, and heteroaryl.Alternatively, R⁵ and R⁶ are taken together with the nitrogen atom towhich they are attached to form an optionally substituted heterocyclic.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt, ester or combination thereof, incombination with a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present invention provides a method for theprevention or treatment of an ASK-1 mediated disease or condition. Themethod comprises administering a therapeutically effective amount of acompound of Formula (I). The present invention also provides the use ofa compound of Formula (I) for the preparation of a medicament for theprevention or treatment of an ASK-1 mediated disease or condition. Suchdiseases include autoimmune disorders, neurodegenerative disorders,inflammatory diseases, chronic kidney disease, cardiovascular disease,metabolic disorders, and acute and chronic liver diseases.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by Formula(I) as described above, or a pharmaceutically acceptable salt or esterthereof.

In certain embodiments of the compounds of Formula (I), X is CH.

In certain embodiments of the compounds of Formula (I), X is CF.

In certain embodiments of the compounds of Formula (I), X is N.

In certain embodiments of the compounds of Formula (I), R¹ is selectedfrom the groups below,

where each of these groups is optionally further substituted.

In certain embodiments, of the compounds of Formula (I), R⁴ is selectedfrom the groups shown below:

where each of these groups is optionally further substituted.

In certain embodiments of the compounds of Formula (I), R² is selectedfrom the groups set forth below:

In certain embodiments, the invention provides compounds represented byFormula (II-a˜II-h) and pharmaceutically acceptable salts and estersthereof:

wherein

R² and R⁴ are as previously defined.

In certain embodiments, the invention provides compounds represented byFormula (III-a˜III-n) and pharmaceutically acceptable salts and estersthereof,

wherein R¹, R² and R⁴ are as previously defined.

In certain embodiments, the invention provides compounds represented byFormula (IV-a˜IV-n) and pharmaceutically acceptable salts and estersthereof,

wherein R¹, R² and R⁴ are previously defined.

In certain embodiments, the present invention provides a method for theprevention or treatment of an ASK-1 mediated disease or condition. Themethod comprises administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to a subject in need thereof. The present invention also provides theuse of a compound of Formula (I), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of anASK-1 mediated disease or condition.

In certain embodiments, the ASK-1 mediated disease or condition is anautoimmune disorder, a neurodegenerative disorder, an inflammatorydisease, chronic kidney disease, renal disease, cardiovascular disease,a metabolic disease, or an acute or chronic liver disease.

In certain embodiments, the chronic liver disease is primary biliarycirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primarysclerosing cholangitis (PSC), drug induced cholestasis, intrahepaticcholestasis of pregnancy, parenteral nutrition associated cholestasis(PNAC), bacterial overgrowth or sepsis associated cholestasis,autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease,nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis(NASH), liver transplant associated graft versus host disease, livingdonor transplant liver regeneration, congenital hepatic fibrosis,choledocholithiasis, granulomatous liver disease, intra- or extrahepaticmalignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher'sdisease, hemochromatosis, or alpha 1-antitrypsin deficiency. In certainembodiments, the gastrointestinal disease is inflammatory bowel disease(IBD) (including Crohn's disease and ulcerative colitis), irritablebowel syndrome (IBS), bacterial overgrowth, malabsorption,post-radiation colitis, or microscopic colitis.

In certain embodiments, the renal disease is diabetic nephropathy, focalsegmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis,chronic glomerulonephritis, chronic transplant glomerulopathy, chronicinterstitial nephritis, or polycystic kidney disease.

In certain embodiments, the cardiovascular disease is atherosclerosis,arteriosclerosis, reperfusion/ischemia in stroke, cardiac hypertrophy,respiratory diseases, heart attacks, myocardial ischemia.

In certain embodiments, the metabolic disease is insulin resistance,Type I and Type II diabetes, or obesity.

In certain embodiments, the chronic kidney disease is polycystic kidneydisease, pyelonephritis, kidney fibrosis and glomerulonephritis.

Yet a further aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “alkyl” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals. Suitable alkyl groups include“C₁-C₃ alkyl”, “C₁-C₆ alkyl”, “C₁-C₁₀ alkyl”, “C₂-C₄ alkyl”, or “C₃-C₆alkyl”, which refer to alkyl groups containing from one to three, one tosix, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atomsrespectively. Examples of C₁-C₈ alkyl radicals include, but are notlimited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, heptyl and octyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. Suitable alkenyl groups include“C₂-C₁₀ alkenyl”, “C₂-C₈ alkenyl”, “C₂-C₄ alkenyl”, or “C₃-C₆ alkenyl”,which refer to alkenyl groups containing from two to ten, two to eight,two to four or three to six carbon atoms respectively. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon triple bond bythe removal of a single hydrogen atom. Suitable alkynyl groups include“C₂-C₁₀ alkynyl,” “C₂-C₈ alkynyl,” “C₂-C₄ alkynyl,” or “C₃-C₆ alkynyl,”which refer to alkynyl groups containing from two to ten, two to eight,two to four or three to six carbon atoms respectively. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl, and the like. The term“cycloalkyl”, as used herein, refers to a monocyclic or polycyclicsaturated carbocyclic ring or a bi- or tri-cyclic group fused, bridgedor spiro system, and the carbon atoms may be optionally oxo-substitutedor optionally substituted with exocyclic olefinic, iminic or oximicdouble bond. Preferred cycloalkyl groups include C₃-C₁₂ cycloalkyl,C₃-C₆ cycloalkyl, C₃-C₈ cycloalkyl and C₄-C₇ cycloalkyl. Examples ofC₃-C₁₂ cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl,4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl,spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, andthe like.

The term “cycloalkenyl”, as used herein, refers to monocyclic orpolycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridgedor spiro system having at least one carbon-carbon double bond and thecarbon atoms may be optionally oxo-substituted or optionally substitutedwith exocyclic olefinic, iminic or oximic double bond. Preferredcycloalkenyl groups include C₃-C₁₂ cycloalkenyl, C₃-C₈ cycloalkenyl orC₅-C₇ cycloalkenyl groups. Examples of C₃-C₁₂ cycloalkenyl include, butnot limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl,bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl,bicyclo[4.2.1]non-3-en-9-yl, and the like.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system thatcomprises at least one aromatic ring. Polycyclic aryls can comprisefused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fusedrings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ringsystem consisting of two rings wherein at least one ring is aromatic;and the two rings can be fused or covalently attached.

As used herein, the term “arylalkyl” means a functional group wherein analkylene chain is attached to an aryl group, e.g., —CH₂CH₂-phenyl. Theterm “substituted arylalkyl” means an arylalkyl functional group inwhich the aryl group is substituted. Similarly, the term“heteroarylalkyl” means a functional group wherein an alkylene chain isattached to a heteroaryl group. The term “substituted heteroarylalkyl”means a heteroarylalkyl functional group in which the heteroaryl groupis substituted.

The term “alkylene” as used herein, refers to a diradical of a branchedor unbranched saturated hydrocarbon chain, typically having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “substituted” as used herein, refers to independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, deuterium, —F, —Cl, —Br, —I,—OH, protected hydroxy, —NO₂, —CN, —NH₂, N₃, protected amino, alkoxy,thioalkoxy, oxo, C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl,-halo-C₁-C₁₂-alkyl, -halo-C₂-C₁₂-alkenyl, -halo-C₂-C₁₂-alkynyl,-halo-C₃-C₁₂-cycloalkyl, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH— heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkynyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH— aryl, —OCONH— heteroaryl, —OCONH— heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂— aryl, —NHCO₂—heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH— C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH— aryl, —SO₂NH— heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl,methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene,C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl,heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. In certainembodiments, the substituents are independently selected from halo,preferably Cl and F; C₁-C₄-alkyl, preferably methyl and ethyl;halo-C₁-C₄-alkyl, such as fluoromethyl, difluoromethyl, andtrifluoromethyl; C₂-C₄-alkenyl; halo-C₂-C₄-alkenyl; C₃-C₆-cycloalkyl,such as cyclopropyl; C₁-C₄-alkoxy, such as methoxy and ethoxy;halo-C₁-C₄-alkoxy, such as fluoromethoxy, difluoromethoxy, andtrifluoromethoxy, —CN; —OH; NH₂; C₁-C₄-alkylamino; di(C₁-C₄-alkyl)amino;and NO₂. It is understood that the aryls, heteroaryls, alkyls, and thelike can be further substituted. In some cases, each substituent in asubstituted moiety is additionally optionally substituted with one ormore groups, each group being independently selected from C₁-C₆-alkyl,—F, —Cl, —Br, —I, —OH, —NO₂, —CN, or —NH₂. Preferably, a substitutedalkyl group, such as a substituted methyl group, is substituted with oneor more halogen atoms, more preferably one or more fluorine or chlorineatoms.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl moiety described herein can also be an aliphatic group, analicyclic group or a heterocyclic group. An “aliphatic group” isnon-aromatic moiety that may contain any combination of carbon atoms,hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, andoptionally contain one or more units of unsaturation, e.g., doubleand/or triple bonds. An aliphatic group may be straight chained,branched or cyclic and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, aliphatic groups include,for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines,and polyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may be used in placeof the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylenegroups described herein.

The term “alicyclic” as used herein, denotes a monovalent group derivedfrom a monocyclic or polycyclic saturated carbocyclic ring compound bythe removal of a single hydrogen atom. Examples include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Such alicyclic groups maybe further substituted.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms connected to the rest of the moleculevia an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy,2-propoxy (isopropoxy) and the higher homologs and isomers. Preferredalkoxy are (C₁-C₃) alkoxy.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above and includes optionally substituted aryl groups as alsodefined above. The term “arylthio” refers to the group R—S—, where R isas defined for aryl.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused, bridged or spiro system, where (i) each ringsystem contains at least one heteroatom independently selected fromoxygen, sulfur and nitrogen, (ii) each ring system can be saturated orunsaturated (iii) the nitrogen and sulfur heteroatoms may optionally beoxidized, (iv) the nitrogen heteroatom may optionally be quaternized,(v) any of the above rings may be fused to an aromatic ring, and (vi)the remaining ring atoms are carbon atoms which may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic,iminic or oximic double bond. Representative heterocycloalkyl groupsinclude, but are not limited to, 1,3-dioxolane, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinoxalinyl, pyridazinonyl,2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl,5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl,and tetrahydrofuryl. Such heterocyclic groups may be furthersubstituted. Heteroaryl or heterocyclic groups can be C-attached orN-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

It will be apparent that in various embodiments of the invention, thesubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, andheterocycloalkyl are intended to be monovalent or divalent. Thus,alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene,cycloalkynylene, arylalkylene, heteroarylalkylene andheterocycloalkylene groups are to be included in the above definitionsand are applicable to provide the Formulas herein with proper valency.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “optionally substituted”, as used herein, means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

In certain embodiments, the compounds of each formula herein are definedto include isotopically labelled compounds. An “isotopically labelledcompound” is a compound in which at least one atomic position isenriched in a specific isotope of the designated element to a levelwhich is significantly greater than the natural abundance of thatisotope. For example, one or more hydrogen atom positions in a compoundcan be enriched with deuterium to a level which is significantly greaterthan the natural abundance of deuterium, for example, enrichment to alevel of at least 1%, preferably at least 20% or at least 50%. Such adeuterated compound may, for example, be metabolized more slowly thanits non-deuterated analog, and therefore exhibit a longer half-life whenadministered to a subject. Such compounds can synthesize using methodsknown in the art, for example by employing deuterated startingmaterials. Unless stated to the contrary, isotopically labelledcompounds are pharmaceutically acceptable.

The compounds described herein can contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus, acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

Berge, et al. describes pharmaceutically acceptable salts in detail inJ. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention, or separately by reaction of the free base function witha suitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts e.g.,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid or malonic acid or by using othermethods used in the art such as ion exchange. Other pharmaceuticallyacceptable salts include, but are not limited to, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, esters ofC₁-C₆-alkanoic acids, such as acetate, propionate, butyrate and pivalateesters.

The term “hydroxy activating group,” as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992) and in “Prodrugs of Alcohols and 2007, pp 31-99.

The term “amino” as used herein, refers to the group —NH₂.

The term “substituted amino” as used herein, refers to the group —NRRwhere each R is independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkylprovided that both R groups are not hydrogen, or a group —Y—Z, in whichY is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, oralkynyl.

The term “amino protecting group” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound, which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the Formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

The term “treating”, as used herein, means relieving, lessening,reducing, eliminating, modulating, or ameliorating, i.e. causingregression of the disease state or condition. Treating can also includeinhibiting, i.e. arresting the development, of an existing disease stateor condition, and relieving or ameliorating, i.e. causing regression ofan existing disease state or condition, for example when the diseasestate or condition may already be present.

The term “preventing”, as used herein means, to completely or almostcompletely stop a disease state or condition, from occurring in apatient or subject, especially when the patient or subject ispredisposed to such or at risk of contracting a disease state orcondition.

Additionally, the compounds of the present invention, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non-stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar to or comparable in function and appearance tothe reference compound.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

The terms “protogenic organic solvent” or “protic solvent” as usedherein, refer to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofprotogenic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods ofPurification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. Additionally, thevarious synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. In addition, the solvents,temperatures, reaction durations, etc. delineated herein are forpurposes of illustration only and variation of the reaction conditionscan produce the desired isoxazole products of the present invention.Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the compoundsdescribed herein include, for example, those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Or anic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995).

The compounds of this invention may be modified by appending variousfunctionalities via synthetic means delineated herein to enhanceselective biological properties. Such modifications include those whichincrease biological penetration into a given biological system (e.g.,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionFormulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or Formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the Formulator.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the Formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theFormulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable Formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableFormulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragées, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical Formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic Formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Abbreviations

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

-   BOP-Cl for bis(2-oxo-3-oxazolidinyl)phosphinic chloride;-   CDI for carbonyldiimidazole;-   DBU for 1,8-diazabicycloundec-7-ene;-   DCC for N,N-dicyclohexylcarbodiimide;-   DCM for dichloromethane;-   DIPEA for N,N-diisopropylethylamine;-   DMAP for N,N-dimethylaminopyridine;-   DME for 1,2-dimethoxyethane;-   DMF for N,N-dimethyl formamide;-   DMPU for 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone;-   EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride;-   Et₃N for triethylamine;-   EtOAc for ethyl acetate;-   HATU for    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate;-   HCl for hydrochloric acid;-   mCPBA for meta-chloroperoxybenzoic acid;-   NMO for N-methylmorpholine-N-oxide;-   PE for petroleum ether-   PhMe for toluene;-   PyAOP for 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium    hexafluorophosphate;-   PyBOP for benzotriazol-1-yl-oxytripyrrolidinophosphonium    hexafluorophosphate;-   THF for tetrahydrofuran.    Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared, which are intended as an illustration only and not to limitthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

As shown in Scheme 1, the ester compound of formula (S-4), wherein R⁴,X, and

have been previously defined, can be prepared under Suzuki-Miyauracoupling conditions either from compound of formula (S-1) andcorresponding boronic esters or acids; or from compound of formula (S-2)with corresponding halides. Alternatively, compound of formula (S-3),which can be prepared by Suzuki-Miyaura coupling conditions, can beconverted to ester compound of formula (S-4) by Pd-catalyzed COinsertion in alcohols. Hydrolysis of compound of formula (S-4) underbasic conditions provides carboxylic acid compound of formula (S-5).

As shown in Scheme 2, treatment of carboxylic acid compound of formula(S-5) and amine compound of formula (S-6) in an aprotic solvent with asuitable coupling reagent in the presence of organic base forms amidecompound of Formula (I), wherein

R⁴, X,

have been previously defined. The suitable coupling reagent can be, suchas, but not limited to, BOP-Cl, CDI, DCC, EDC, HATU, PyAOP or PyBOP. Theorganic base can be, such as, but not limited to, Et₃N, DIPEA, pyridineor N-methyl morpholine. The aprotic solvent can be, such as, but notlimited to, THF, DCM and DMF. The reaction temperature is from −20° C.to 80° C.

As shown in Scheme 3, the carboxylic acid compound of formula (S-5) canbe first converted to acyl chloride compound of formula (S-7), usingsuch as, but not limited to, oxalyl chloride or Ghosez reagent.Treatment of the acyl chloride (S-7) with amine compound of formula(S-6) in the presence of organic base, such as pyridine, providescompound of formula (I), wherein

R⁴, X,

have been previously defined.

As shown in Scheme 4, amide compound of formula (I), wherein

R⁴, X,

have been previously defined, can also be prepared from ester compoundof formula (S-4) and amine compound of formula (S-6) under ester-amideexchange conditions. These conditions include, but not limited to,Cs₂CO₃ or K₂CO₃ in DMF at elevated temperature; or AIMe₃ in DCM atambient or elevated temperature.

EXAMPLES Example 1

Step 1-1

To a solution of ethyl 4-hydroxypyridine-2-carboxylate (200 mg, 1.20mmol) in DCM (5 mL) at 0° C. was added triethylamine (242.1 mg, 2.39mmol) and Tf₂O (506.3 mg, 1.79 mmol) dropwise. The mixture was warmed toroom temperature and stirred for 1 hour, and concentrated in vacuo.Purification of the residue by silica gel column chromatography with0-20% EtOAc in PE afforded compound 1-a (170 mg, 47.49%) as a yellowoil.

Step 1-2

A mixture of compound 1-a (150 mg, 0.50 mmol),1-cyclopropyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (234.7mg, 1.00 mmol), Pd(PPh₃)₄ (57.9 mg, 0.05 mmol) and K₂CO₃ (138.6 mg, 1.00mmol) in dioxane (5 mL) was stirred at 100° C. under nitrogen atmospherefor 1 h. Solvent was removed under vacuum. Purification of the residueby silica gel chromatography with EtOAc in PE (0-50%) afforded compound1-b (60 mg, 46.52%) as yellow oil.

Step 1-3

A mixture of compound 1-b (60 mg, 0.23 mmol), compound 1-c (71.4 mg,0.35 mmol) and Cs₂CO₃ (152.0 mg, 0.47 mmol) in DMF was stirred at 120°C. for 2 h. Solvent was removed under vacuum. Purification of theresidue by C-18 column with CH₃CN in H₂O (60-70%) afforded Example 1(7.8 mg) as a white solid. [M+H]⁺, 416. ¹H NMR (400 MHz, Chloroform-d) δ10.61 (s, 1H), 8.65-8.61 (m, 2H), 8.40 (s, 1H), 8.12 (d, J=7.6 Hz, 1H),8.04-8.01 (m, 3H), 7.62 (dd, J=5.3, 1.6 Hz, 1H), 5.89 (m, 1H), 3.72 (m,1H), 1.76 (d, J=6.6 Hz, 6H), 1.23 (m, 2H), 1.14 (m, 2H).

Example 2

Step 2-1

At 0° C. Tf₂O (1.86 g, 6.60 mmol) was added dropwise to a solution ofethyl 4-hydroxy-5-methylpyridine-2-carboxylate (800 mg, 4.42 mmol) andEt₃N (1.33 g, 13.20 mmol) in DCM (5 mL). The resulting mixture wasstirred at room temperature for 1 h and concentrated under vacuum.Purification of the residue by silica gel column chromatography withEtOAc in PE (0-24%) afforded compound 2-a (550 mg, 39.8%) as a yellowoil.

Step 2-2

A mixture of compound 2-a (550 mg, 1.76 mmol),1-cyclopropyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (822.1mg, 3.51 mmol), Pd(PPh₃)₄ (202.9 mg, 0.18 mmol) and K₂CO₃ (485.3 mg,3.51 mmol) in dioxane (10 mL) was stirred at 100° C. for 2 h undernitrogen atmosphere. Solvent was removed under vacuum. The residue waspurified by silica gel column chromatography with EtOAc in PE (0-35%) toafford compound 2-b (400 mg, 83.97%) as a yellow oil.

Step 2-3

A mixture of compound 2-b (80 mg, 0.29 mmol), compound 1-c (90.3 mg,0.44 mmol) and Cs₂CO₃ (192.1 mg, 0.59 mmol) in DMF (2 mL) was stirred at100° C. for 1 h. Solvent was removed under vacuum. The crude product waspurified by C18 column with CH₃CN in H₂O (50-70%) to afford Example 2(15.3 mg) as a white solid. [M+H]⁺, 430; ¹H NMR (400 MHz, Chloroform-d)δ 10.54 (s, 1H), 8.61 (d, J=8.3 Hz, 1H), 8.52 (s, 1H), 8.31 (s, 1H),8.09 (d, J=8.3 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.87 (s, 2H), 5.88 (m,1H), 3.72 (m, 1H), 2.57 (s, 3H), 1.75 (d, J=6.7 Hz, 6H), 1.24 (m, 2H),1.16 (m, 2H).

Example 3

Step 3-1

To a mixture of1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.0 g, 8.55 mmol), 2-chloro-5-fluoro-4-iodopyridine (2 g, 7.77 mmol),and K₂CO₃ (3.2 g, 23.31 mmol) in dioxane (10 mL) and H₂O (2 mL) wasadded Pd(dppf)Cl₂ (568.5 mg, 0.78 mmol) at room temperature undernitrogen atmosphere. The resulting mixture was stirred at 80° C. for 3 hunder nitrogen. After cooling to room temperature, the mixture wasdiluted with EtOAc (20 mL) and washed with water (10 mL*2) and brine (10mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, andwas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography with PE/EtOAc (5:1) to afford compound3-a (1.3 g, 70.41%) as a white solid.

Step 3-2

In a 50 mL autoclave a solution of compound 3-a (1.2 g, 5.0 mmol),Pd(dppf)Cl₂ (385 mg, 0.5 mmol), and Et₃N (1.52 g, 15 mmol) in BuOH (20mL) was saturated with CO and stirred under 10 atm of CO at 70° C. for16 hours. The resulting mixture was concentrated under reduced pressure.The residue was purified by silica gel column chromatography withPE/EtOAc (3:1) to afford compound 3-b (1.2 g, 78.35%) as a yellow oil.

Step 3-3

A solution of compound 3-b (600 mg, 1.98 mmol) in acetonitrile (5 mL)was treated with 1N HCl (5 mL) and the resulting mixture was stirred at100° C. for 14 h under nitrogen atmosphere. Solvent was removed underreduced pressure. The residue was purified by reverse flashchromatography with 0-30% MeCN in water to afford compound 3-c (420 mg,85.79%) as a white solid.

Step 3-4

To a solution of compound 3-c (250 mg, 1.01 mmol), HATU (499.8 mg, 1.31mmol) and DIPEA (392.1 mg, 3.03 mmol) in DMF (5 mL) was added compound1-c (227.2 mg, 1.11 mmol). The resulting mixture was stirred at roomtemperature for 4 h under nitrogen atmosphere. The residue was purifiedby reverse-phase flash chromatography with 40-70% MeCN in water toafford Example 3 (150 mg, 34.22%) as an off-white solid. [M+H]⁺, 434; ¹HNMR (400 MHz, Chloroform-d) δ 10.39 (s, 1H), 8.60 (dd, J=8.4, 1.0 Hz,1H), 8.53-8.51 (m, 2H), 8.12-8.09 (m, 3H), 8.02 (t, J=8.0 Hz, 1H), 5.85(m, 1H), 3.73 (m, 1H), 1.76 (d, J=6.7 Hz, 6H), 1.26 (m, 2H), 1.12 (m,2H).

Example 4

Step 4-1

DBU (0.2 mL) was added to a solution of Example 3 (30 mg, 0.07 mmol) inpyrrolidine (1 mL). The resulting mixture was stirred at 80° C. for 4 hunder nitrogen atmosphere. The reaction mixture was purified by reversephase flash chromatography with 40-70% MeCN in water to afford Example 4(17.9 mg, 53.37%) as a white solid. [M+H]⁺, 434; ¹H NMR (400 MHz,Chloroform-d) δ 10.39 (s, 1H), 8.60 (dd, J=8.3, 1.0 Hz, 1H), 8.20 (s,1H), 8.04-8.06 (m, 2H), 7.97 (t, J=8.0 Hz, 1H), 7.68 (m, 2H), 5.90 (m,1H), 3.69 (m, 1H), 3.20 (m, 4H), 1.95 (m, 4H), 1.75 (d, J=6.7 Hz, 6H),1.26 (m, 2H), 1.12 (m, 2H).

Example 5

Example 5 was prepared following a similar protocol as Example 4.[M+H]⁺, 499; ¹H NMR (400 MHz, Chloroform-d) δ 10.47 (s, 1H), 8.61 (d,J=8.3 Hz, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H),8.08 (d, J=7.4 Hz, 1H), 7.99 (t, J=8.0 Hz, 1H), 5.88 (m, 1H), 3.71 (m,1H), 3.03 (m, 4H), 1.76-1.70 (m, 10H), 1.70 (m, 2H), 1.26 (m, 2H), 1.14(m, 2H).

Example 6

Example 6 was prepared following a similar protocol as Example 4.[M+H]⁺, 501; ¹H NMR (400 MHz, Chloroform-d) δ 10.45 (s, 1H), 8.60 (dd,J=8.3, 1.0 Hz, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.18-8.15 (m, 2H), 8.09(dd, J=7.7, 1.0 Hz, 1H), 8.00 (t, J=8.3 Hz, 1H), 5.87 (m, 1H), 3.88 (t,J=4.4 Hz, 4H), 3.70 (m, 1H), 3.11 (t, J=4.4 Hz, 4H), 1.75 (d, J=6.7 Hz,6H), 1.70 (m, 2H), 1.26 (m, 2H), 1.14 (m, 2H).

Example 7

Example 7 was prepared following a similar protocol as Example 4.[M+H]⁺, 501; ¹H NMR (400 MHz, Chloroform-d) δ 10.45 (s, 1H), 8.59 (dd,J=8.3, 1.0 Hz, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.09 (dd,J=7.6, 0.8 Hz, 1H), 7.99 (t, J=8.0 Hz, 1H), 5.88 (m, 1H), 3.71 (m, 1H),3.19 (t, J=4.4 Hz, 4H), 2.71 (t, J=4.4 Hz, 4H), 2.47 (s, 3H), 1.75 (d,J=6.7 Hz, 6H), 1.26 (m, 2H), 1.14 (m, 2H).

Example 8

Step 8-1

To a solution of compound 3-c (150 mg, 0.61 mmol), HATU (348 mg, 0.91mmol) and DIPEA (239 mg, 1.87 mmol) in DMF (5 mL) was added compound 8-a(141 mg, 0.67 mmol) at room temperature under nitrogen atmosphere. Thereaction mixture was stirred at rt for 2 h, and purified by reversephase flash chromatography win 50-80% MeCN in water to afford Example 8(130 mg, 48.8%) as a white solid. [M+H]⁺ 440; ¹H NMR (400 MHz,Chloroform-d) δ 10.58 (s, 1H), 8.51-8.50 (m, 2H), 8.17 (s, 1H),8.11-8.08 (m, 2H), 5.88 (m, 1H), 3.73 (m, 1H), 1.74 (d, J=6.7 Hz, 6H),1.25 (m, 2H), 1.16 (m, 2H).

Example 9

Example 9 was prepared following a similar protocol as shown in Step4-1. [M+H]⁺ 491; ¹H NMR (400 MHz, Chloroform-d) δ 10.58 (s, 1H), 8.18(s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.69-7.67 (m, 2H), 5.91 (m, 1H),3.69 (m, 1H), 3.20 (t, J=6.4 Hz, 4H), 1.95 (t, J=6.4 Hz, 4H), 1.74 (d,J=6.7 Hz, 6H), 1.25 (m, 2H), 1.12 (m, 2H).

Example 10

Example 10 was prepared following a similar protocol as shown in Step4-1. [M+H]⁺ 507; ¹H NMR (400 MHz, Chloroform-d) δ 10.62 (s, 1H), 8.37(s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.17-8.15 (m, 2H), 5.88 (m, 1H),3.88 (t, J=4.4 Hz, 4H), 3.70 (m, 1H), 3.11 (t, J=4.4 Hz, 4H), 1.74 (d,J=6.6 Hz, 6H), 1.22 (m, 2H), 1.15 (m, 2H).

Example 11

Example 11 was prepared following a similar protocol as shown in Step4-1. [M+H]⁺ 505; ¹H NMR (400 MHz, Chloroform-d) δ 10.63 (s, 1H), 8.36(s, 1H), 8.24 (s, 1H), 8.22-8.12 (m, 3H), 5.89 (m, 1H), 3.71 (m, 1H),3.02 (t, J=5.2 Hz, 4H), 1.74-1.63 (m, 12H), 1.25 (m, 2H), 1.16 (m, 2H).

Example 12

Example 12 was prepared following a similar protocol as shown in Step4-1. [M+H]⁺ 520; ¹H NMR (400 MHz, Chloroform-d) δ 10.62 (s, 1H), 8.39(s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 5.88(m, 1H), 3.71 (m, 1H), 3.22 (t, J=4.9 Hz, 4H), 2.79 (s, 4H), 2.51 (s,3H), 1.74 (d, J=6.7 Hz, 6H), 1.25 (m, 2H), 1.16 (m, 2H).

Example 13

Step 13-1

A mixture of methyl 4-chloro-5-methylpyridine-2-carboxylate (200 mg,1.08 mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(302.7 mg, 1.29 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (88.0 mg, 0.11 mmol), andK₂CO₃ (446.8 mg, 3.23 mmol) in dioxane (4 mL) and water (1 mL) wasstirred at 80° C. for 2 h under nitrogen atmosphere. After cooling toroom temperature, the residue was purified by reverse phase flashchromatography with 40-70% MeCN in H₂O to afford compound 13-a (60 mg,21.64%) as a yellow solid.

Step 13-2

To a stirred mixture of compound 13-a (60 mg, 0.23 mmol) in MeOH (2 mL)and H₂O (1 mL) was added NaOH (18.7 mg, 0.47 mmol) at 0° C. Theresulting mixture was stirred for 1 h at 50° C., cooled to rt, acidifiedto pH 3 with HCl (aq.), and concentrated under vacuum. The residue waspurified by reverse phase flash chromatography with 10-50% MeCN/H₂O toafford compound 13-b (40 mg, 70.51%) as a white solid.

Step 13-3

To a solution of compound 13-b (40 mg, 0.16 mmol), HATU (91 mg, 0.24mmol), and DIPEA (62 mg, 0.48 mmol) in DMF (2 mL) was added compound13-c (52 mg, 0.20 mmol). The reaction mixture was stirred at roomtemperature for 16 h, and then purified by reverse phase flashchromatography with the 10-80% MeCN/H₂O to afford compound 13-d (30 mg,37.4%) as a white solid.

Step 13-4

To a solution of compound 13-d (30 mg, 0.06 mmol) in MeOH (2 ml) wasadded K₂CO₃ (42 mg, 0.3 mmol). The reaction was stirred at rt for 2 h.Solid was removed by filtration. The filtrate was purified by reversephase flash chromatography with 10-60% MeCN/H₂O to afford Example 13 (30mg) as a white solid. [M+H]+ 446; ¹H NMR (400 MHz, Chloroform-d) δ 10.56(s, 1H), 8.51 (s, 1H), 8.40 (dd, J=8.3, 1.0 Hz, 1H), 8.30 (s, 1H), 8.12(dd, J=8.3, 1.0 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.87 (s, 2H), 5.91 (m,1H), 4.19 (d, J=5.6 Hz, 2H), 3.72 (m, 1H), 3.27 (s, 1H), 2.57 (s, 3H),1.74 (d, J=6.8 Hz, 3H), 1.25 (m, 2H), 1.16 (m, 2H).

Example 14

Step 14-1

A mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1 g, 3.25mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(990 mg, 4.23 mmol), Pd(dppf)Cl₂ (375 mg, 0.3 mmol), and potassiumcarbonate (1.35 g, 9.75 mmol) in ethylene glycol dimethyl ether (5 mL)and H₂O (5 mL) was stirred at 100° C. for 3 hours. The reaction mixturewas concentrated, and purified by Prep-HPLC with 0-100% MeCN/H₂O toafford compound 14-a (750 mg, 80%) as a yellow solid.

Step 14-2

In a 50-mL autoclave a solution of compound 14-a (750 mg, 2.61 mmol),Pd(dppf)Cl₂ (425 mg, 0.52 mmol), and TEA (957 mg, 7.83 mmol) in BuOH (10mL) was stirred under 10 atm of CO at 70° C. overnight. The reactionmixture was concentrated in vacuo. Purification of the residue byPrep-HPLC with 0-100% MeCN/H₂O provided compound 14-b (660 mg, 72%) as ayellow solid.

Step 14-3

In a 50-mL autoclave aq. 1N HCl (5 mL) was added to a solution ofcompound 14-b (660 mg, 1.87 mmol) in MeCN (10 mL). The resultingsolution was stirred at 100° C. overnight. The reaction mixture wasconcentrated, and the residue was purified by Prep-HPLC with 0-40%MeCN/H₂O to afford compound 14-c (420 mg, 76%) as a white solid.

Step 14-4

To a solution of compound 14-c (30 mg, 0.10 mmol), HATU (58 mg, 0.15mmol), and 4-methylmorpholine (33 mg, 0.30 mmol) in DMF (2 mL) was addedcompound 1-c (24.8 mg, 0.12 mmol). The resulting mixture was stirred atroom temperature overnight, and purified by Prep-HPLC with 0-80%MeCN/H₂O to afford Example 14 (16.5 mg) as a white solid. [M+H]⁺ 484; ¹HNMR (400 MHz, Chloroform-d) δ 10.48 (s, 1H), 9.01 (s, 1H), 8.60 (d,J=8.4, 1.0 Hz, 1H), 8.43 (s, 1H), 8.15 (dd, J=8.4, 1.0 Hz, 1H), 8.04 (t,J=8.4 Hz, 1H), 7.89 (d, J=13.1 Hz, 2H), 5.86 (m, 1H), 3.73 (m, 1H), 1.76(d, J=6.7 Hz, 6H), 1.25 m, 2H), 1.16 (m, 2H).

Example 15

Step 15-1

Example 15 was prepared following a similar protocol as shown in Step14-4. [M+H]⁺ 490; ¹H NMR (400 MHz, Chloroform-d) δ 10.69 (s, 1H), 8.98(s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 7.89 (d, J=14.2 Hz, 2H), 5.87 (m,1H), 3.73 (m, 1H), 1.75 (d, J=6.7 Hz, 6H), 1.25 (m, 2H), 1.16 (m, 2H)

Example 16

Example 16 was prepared from compound 14-c following similar protocol asshown in Step 13-3 and Step 13-4. [M+H]⁺ 500; ¹H NMR (400 MHz,Chloroform-d) δ 10.51 (s, 1H), 9.00 (s, 1H), 8.44 (m, 2H), 8.17 (dd,J=8.0, 1.0 Hz, 1H), 8.05 (t, J=8.0 Hz, 1H), 7.90 (d, J=14.3 Hz, 2H),5.88 (m, 1H), 4.20 (m, 2H), 3.73 (m, 1H), 1.74 (d, J=6.8 Hz, 3H), 1.23(m, 2H), 1.14 (m, 2H).

Example 17

Example 17 was prepared from compound 13-b and compound 17-a followingsimilar protocol as shown in Step 14-4. [M+H]⁺ 430; ¹H NMR (400 MHz,Chloroform-d) δ 10.55 (s, 1H), 8.60 (d, J=8.3 Hz, 1H), 8.52 (s, 1H),8.30 (s, 1H), 8.06 (t, J=8.1 Hz, 1H), 7.87 (s, 2H), 7.68 (d, J=7.8 Hz,1H), 3.98 (m, 1H), 3.72 (m, 1H), 2.56 (s, 3H), 1.53 (d, J=6.9 Hz, 6H),1.25 (m, 2H), 1.15 (m, 2H).

Example 18

Step 18-1

A mixture of compound 18-a (US 2017/0121308) (100 mg, 0.45 mmol),1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (211mg, 0.90 mmol), Pd(PPh₃)₄ (104 mg, 0.09 mmol), and K₂CO₃ (187 mg, 1.35mmol) in dioxane (5 mL) was stirred at 100° C. for overnight undernitrogen atmosphere. Solvent was evaporated under vacuum, and theresidue was purified by reverse phase column with 0-65% MeCN/H₂O toafford compound 18-b (95 mg, 71.8%) as a yellow solid.

Step 18-2

To an 8 mL seal tube were added compound 18-b (30 mg, 0.10 mmol),compound 1-c (43.0 mg, 0.20 mmol), Cs₂CO₃ (100 mg, 0.31 mmol) and DMF (5mL). The resulting mixture was stirred at 100° C. for 3 hours undernitrogen atmosphere, and purified by reverse phase flash chromatographywith 0-65% MeCN/H₂O to afford Example 18 (8 mg) as an off-white solid.[M+H]⁺ 466; ¹H NMR (400 MHz, Chloroform-d) δ 10.54 (s, 1H), 9.03 (s,1H), 8.61 (dd, J=8.4, 0.9 Hz, 1H), 8.39 (s, 1H), 8.14 (dd, J=8.4, 0.9Hz, 1H), 8.03 (t, J=8.4 Hz, 1H), 7.91-7.82 (m, 2H), 6.84 (t, J=54.0 Hz,1H), 5.87 (m, 1H), 3.74 (m, 1H), 1.77 (d, J=6.7 Hz, 6H), 1.26 (m, 2H),1.19 (m, 2H).

Example 19

Example 19 was prepared from compound 18-b and compound 8-a followingsimilar protocol as shown in Step 18-2. [M+H]+ 472; ¹H NMR (400 MHz,Chloroform-d) δ 10.73 (s, 1H), 9.00 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H),7.86 (d, J=17.1 Hz, 2H), 6.84 (t, J=54.0 Hz, 1H), 5.88 (m, 1H), 3.74 (m,1H), 1.75 (d, J=6.7 Hz, 6H), 1.26 (m, 2H), 1.17 (m, 2H).

Example 20

Step 20-1

A mixture of methyl 4-chloro-5-methylpyridine-2-carboxylate (300 mg,1.62 mmol),1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(606.5 mg, 2.42 mmol), Pd(PPh₃)₄ (373.5 mg, 0.32 mmol), K₂CO₃ (670.1 mg,4.85 mmol) in dioxane (5 mL) was stirred at 100° C. under nitrogenatmosphere overnight. The mixture was cooled to room temperature andpurified by reverse phase flash chromatography with 0-40% MeCN/H₂O toafford compound 20-a (140 mg, 31.69%) as a yellow oil.

Step 20-2

Example 20 was prepared from compound 20-a and compound 1-c followingsimilar protocol as shown in Step-18-2. [M+H]⁺ 446; ¹H NMR (400 MHz,Chloroform-d) δ 10.57 (s, 1H), 8.62 (d, J=8.2 Hz, 1H), 8.53 (s, 1H),8.34 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 7.94 (s,2H), 5.89 (m, 1H), 2.59 (s, 3H), 1.76 (d, J=6.6 Hz, 6H), 1.70 (s, 9H).

Example 21

Example 21 was prepared from compound 20-a and 17-a following similarprotocol as show in Step 18-2. [M+H]+ 446; ¹H NMR (400 MHz,Chloroform-d) δ 10.58 (s, 1H), 8.61 (d, J=8.2 Hz, 1H), 8.53 (s, 1H),8.33 (s, 1H), 8.07 (t, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.69(d, J=7.7 Hz, 1H), 4.00 (m, 1H), 2.59 (s, 3H), 1.71 (s, 9H), 1.54 (d,J=6.9 Hz, 6H).

Example 22

Example 22 was prepared from compound 20-a and compound 22-a followingsimilar protocol as show in Step 18-2. [M+H]⁺ 462; ¹H NMR (400 MHz,Chloroform-d) δ 10.60 (s, 1H), 8.51 (s, 1H), 8.41 (d, J=8.3 Hz, 1H),8.33 (s, 1H), 8.13 (d, J=7.6 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.93 (s,1H), 7.92 (s, 1H), 5.90 (m, 1H), 4.19 (d, J=6.0 Hz, 2H), 2.59 (s, 3H),1.74 (d, J=7.6 Hz, 3H), 1.69 (s, 9H).

Example 23

Step 23-1

A mixture of methyl5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate(300 mg, 1.08 mmol), 4-bromo-1-(propan-2-yl)-1H-imidazole (307.0 mg,1.62 mmol), Pd(PPh₃)₄ (250.2 mg, 0.22 mmol), K₂C₀₃ (448.8 mg, 3.25 mmol)in dioxane (5 ml) was stirred at 100° C. under nitrogen atmosphereovernight. The resulting mixture was concentrated under vacuum andpurified by reverse phase flash chromatography with 0-37% MeCN/H₂O toafford compound 23-a (180 mg, 64.12%) as yellow oil.

Step 23-2

Example 23 was prepared from compound 23-a following similar protocol asshown in Step 18-2. [M+H]⁺ 432; ¹H NMR (400 MHz, Chloroform-d) δ 10.57(s, 1H), 8.68 (s, 1H), 8.63 (d, J=8.4 Hz, 1H), 8.51 (s, 1H), 8.08 (d,J=7.5 Hz, 1H), 7.99 (t, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 5.90(m, 1H), 4.46 (m, 1H), 2.68 (s, 3H), 1.75 (d, J=6.6 Hz, 6H), 1.60 (d,J=6.7 Hz, 6H).

Example 24

Example 24 was prepared from compound 23-a and compound 17-a followingsimilar protocol as shown in Step 18-2. [M+H]⁺ 432; ¹H NMR (400 MHz,Chloroform-d) δ 10.58 (s, 1H), 8.69 (s, 1H), 8.62 (d, J=8.2 Hz, 1H),8.51 (s, 1H), 8.05 (t, J=8.1 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J=7.6 Hz,1H), 7.44 (d, J=1.3 Hz, 1H), 4.47 (m, 1H), 4.00 (m, 1H), 2.68 (s, 3H),1.61 (d, J=6.7 Hz, 6H), 1.53 (d, J=6.9 Hz, 6H).

Example 25

Example 25 was prepared from compound 23-a and compound 22-a followingsimilar protocol as shown in Step 18-2. [M+H]⁺ 448; ¹H NMR (400 MHz,Chloroform-d) δ 10.61 (s, 1H), 8.68 (s, 1H), 8.51 (s, 1H), 8.38 (d,J=8.3 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.76 (s,1H), 7.45 (s, 1H), 5.94 (m, 1H), 4.48 (m, 1H), 4.17 (m, 2H), 2.68 (s,3H), 1.74 (d, J=6.8 Hz, 3H), 1.62 (d, J=6.7 Hz, 6H).

Example 26

Example 26 was prepared following similar protocol as shown in example20. [M+H]⁺ 432; ¹H NMR (400 MHz, Chloroform-d) δ 10.55 (s, 1H), 8.62 (d,J=8.3 Hz, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.01(t, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 5.88 (m, 1H), 4.62 (m,1H), 2.58 (s, 3H), 1.76 (d, J=6.6 Hz, 6H), 1.62 (d, J=6.7 Hz, 6H).

Example 27

Example 27 was prepared following similar protocol as shown in example21. [M+H]⁺ 432; ¹H NMR (400 MHz, Chloroform-d) δ 10.63 (s, 1H), 8.60 (d,J=8.3 Hz, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.07 (t, J=8.1 Hz, 1H), 7.92(s, 1H), 7.86 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 4.64 (m, 1H), 4.02 (m,1H), 2.59 (s, 3H), 1.63 (d, J=6.7 Hz, 6H), 1.54 (d, J=6.9 Hz, 6H).

Example 28

Example 28 was prepared following similar protocol as shown in example22. [M+H]⁺ 448; ¹H NMR (400 MHz, Chloroform-d) δ 10.69 (s, 1H), 8.52 (s,1H), 8.41 (d, J=8.0 Hz, 1H), 8.33 (s, 1H), 8.15 (d, J=7.1 Hz, 1H), 8.02(t, J=8.0 Hz, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 5.94 (m, 1H), 4.63 (m,1H), 4.19 (m, 2H), 2.60 (s, 3H), 1.74 (d, J=6.8 Hz, 3H), 1.63 (d, J=6.7Hz, 6H).

Example 29

Step 29-1

To a solution of compound 22-a (60.1 mg, 0.27 mmol) in DCM (5 mL) at 0°C. was added Me₃Al in toluene (0.4 mL, 0.568 mmol) under nitrogenatmosphere. The mixture was stirred for 1 hour and a solution ofcompound 18-b (80 mg, 0.27 mmol) in DCM (1 mL) was added. The resultingmixture was stirred at 35° C. for 16 h, diluted with DCM, and washedwith Rochelles salt and brine. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by prep-HPLC with 35-60% MeCN/H₂O to afford Example29 (11.8 mg) as a white solid. [M+H]⁺ 482; ¹H NMR (400 MHz,Chloroform-d) δ 10.57 (s, 1H), 9.02 (s, 1H), 8.46-8.37 (m, 2H), 8.17 (d,J=7.6 Hz, 1H), 8.05 (t, J=8.1 Hz, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 6.84(t, J=53.2 Hz, 1H), 5.90 (m, 1H), 4.27-4.17 (m, 2H), 3.75 (m, 1H), 1.75(d, J=6.8 Hz, 3H), 1.27 (m, 2H), 1.17 (m, 2H).

Example 30

A mixture of methyl5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (300mg, 1.08 mmol), 4-bromo-1-(trifluoromethyl)-1H-pyrazole (256 mg, 1.19mmol), Pd(PPh₃)₄ (104 mg, 0.1 mmol) and K₂CO₃ (447 mg, 3.24 mmol) indioxane (10 mL) was stirred at 100° C. under nitrogen atmosphere for 1h. Solvent was removed under reduced pressure. The residue was purifiedby reverse phase flash chromatography with 0-60% CH₃CN in water toafford compound 30-a (175 mg, 56.7%) as a white solid.

Step 30-2

Example 30 was prepared from compound 30-a and compound 1-c followingsimilar protocol as shown in Step 29-1. [M+1]+458; ¹H NMR (400 MHz,Chloroform-d) δ 10.50 (s, 1H), 8.62-8.60 (m, 2H), 8.33 (s, 1H), 8.18 (s,1H), 8.15-8.06 (m, 2H), 8.01 (t, J=8.0 Hz, 1H), 5.87 (m, 1H), 2.58 (s,3H), 1.76 (d, J=6.7 Hz, 6H).

Example 31

Example 31 was prepared from compound 30-a and compound 17-a followingsimilar protocol as shown in Step 29-1. [M+1]+458; ¹H NMR (400 MHz,Chloroform-d) δ 10.51 (s, 1H), 8.61-8.59 (m, 2H), 8.32 (s, 1H), 8.17 (s,1H), 8.13 (s, 1H), 8.08 (t, J=8.1 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 3.97(m, 1H), 2.58 (s, 3H), 1.53 (d, J=6.9 Hz, 7H).

Example 32

Example 32 was prepared from compound 30-a and compound 22-a followingsimilar protocol as shown in Step 29-1. [M+1]+474; ¹H NMR (400 MHz,Chloroform-d) δ 10.53 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=8.3 Hz, 1H),8.33 (s, 1H), 8.18 (s, 1H), 8.16-8.13 (m, 2H), 8.02 (t, J=8.0 Hz, 1H),5.90 (m, 1H), 4.21 (m, 2H), 2.59 (s, 3H), 1.74 (d, J=6.8 Hz, 3H).

Example 33

Step 33-1

A mixture of methyl5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate(250 Ng, 0.90 mmol), 3-bromo-1-(propan-2-yl)-H-pyrazole (341.1 g, 1.80mmol), Pd(PPh₃)₄ (208.5 mg, 0.18 mmol), and K₂CO₃ (374.0 mg, 2.71 mmol)in dioxane (5 mL) was stirred at 100° C. under nitrogen atmosphereovernight. The reaction mixture was concentrated under reduced pressure.The residue was purified by reverse phase flash chromatography with0-40% MeCN/H₂O to afford compound 33-a (200 mg, 85.50%) as a yellow oil.

Step 33-2

Example 33 was prepared from compound 33-a and compound 1-c followingsimilar protocol as shown in Step 29-1. [M+H]⁺ 432. ¹H NMR (400 MHz,Chloroform-d) δ 10.60 (s, 1H), 8.67-8.59 (m, 2H), 8.56 (s, 1H), 8.10 (d,J=7.6 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 6.70 (d,J=2.4 Hz, 1H), 5.92 (m, J=6.7 Hz, 1H), 4.61 (m, J=6.7 Hz, 1H), 2.70 (s,3H), 1.76 (d, J=6.6 Hz, 6H), 1.61 (d, J=6.6 Hz, 6H).

Example 34

Example 34 was prepared from compound 33-a and compound 17-a followingsimilar protocol as shown in Step 29-1. [M+H]⁺ 432. ¹H NMR (400 MHz,Chloroform-d) δ 10.58 (s, 1H), 8.65-8.57 (m, 2H), 8.54 (s, 1H), 8.05 (t,J=8.0 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 6.69 (d,J=2.3 Hz, 1H), 4.60 (m, J=6.8 Hz, 1H), 4.00 (m, J=6.9 Hz, 1H), 2.69 (s,3H), 1.61 (d, J=6.7 Hz, 6H), 1.54 (d, J=6.9 Hz, 6H).

Example 35

Example 35 was prepared from compound 33-a and compound 22-a followingsimilar protocol as shown in Step 29-1. [M+H]⁺ 448. ¹H NMR (400 MHz,Chloroform-d) δ 10.63 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.42 (d,J=8.3 Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.56 (d,J=2.3 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 5.94 (m, J=6.5 Hz, 1H), 4.60 (m,J=6.7 Hz, 1H), 4.19 (d, J=6.0 Hz, 2H), 3.30 (s, 1H), 2.70 (s, 3H), 1.74(d, J=6.8 Hz, 3H), 1.61 (d, J=6.7 Hz, 6H)

Example 36

Step 36-1

In a microwave vial a mixture of methyl4-chloro-5-methylpyridine-2-carboxylate (100 mg, 0.54 mmol),2-(tributylstannyl) pyridine (190 mg, 0.52 mmol), and Pd(PPh₃)₄ (49 mg,0.04 mmol) in DMF (2 mL) was heated in microwave at 160° C. for 1 hour.Solvent was removed in vacuo and the residue was purified by prep-HPLCwith 0-90% MeCN/H₂O to afford 60 mg (49%) compound 36-a.

Step 36-2

Example 36 was prepared from compound 36-a and compound 1-c following asimilar protocol as shown in Step 18-2. [M+H]+ 401; ¹H NMR (400 MHz,Chloroform-d) δ 10.55 (s, 1H), 8.79 (d, J=4.4 Hz, 1H), 8.67-8.59 (m,2H), 8.39 (s, 1H), 8.10 (d, J=7.2 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.90(td, J=7.8, 1.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.41 (dd, J=7.6, 4.9Hz, 1H), 5.90 (m, 1H), 2.55 (s, 3H), 1.77 (d, J=6.7 Hz, 6H).

Example 37

Step 37-1

A mixture of methyl 4-chloro-5-methylpyridine-2-carboxylate (100 mg,0.54 mmol), (pyridin-3-yl)boronic acid (100 mg, 0.80 mmol), Pd(PPh₃)₄(62 mg, 0.05 mmol), and K₂CO₃ (224 mg, 1.62 mmol) in dioxane (5 mL) wasstirred at 100° C. overnight. Solvent was removed in vacuo and theresidue was purified by prep-HPLC with 0-80% MeCN/H₂O to provide 60 mg(48.8%) of compound 37-a as a yellow solid.

Step 37-2

Example 37 was prepared from compound 37-a following a similar protocolas shown in Step 18-2. [M+H]⁺ 401; ¹H NMR (400 MHz, Chloroform-d) δ10.52 (s, 1H), 8.75 (d, J=4.8 Hz, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 8.61(d, J=8.0 Hz, 1H), 8.24 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 8.01 (t, J=8.0Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.8, 4.8 Hz, 1H), 5.88 (m,1H), 2.45 (s, 3H), 1.77 (d, J=6.7 Hz, 6H).

Example 38

Step 38-1

A mixture of methyl 4-chloro-5-methylpyridine-2-carboxylate (100 mg,0.54 mmol), (pyridin-4-yl)boronic acid (100 mg, 0.80 mmol), Pd(PPh₃)₄(62 mg, 0.05 mmol), and K₂CO₃ (223 mg, 1.62 mmol) in ethylene glycoldimethyl ether (5 mL) and H₂O (1 mL) was stirred at 100° C. overnight.Solvent was removed in vacuo and the residue was purified by prep-HPLCwith 0-60% MeCN/H₂O to afford 70 mg (61%) of compound 38-a as a yellowsolid.

Step 38-2

Compound 1-c (57 mg, 0.28 mmol) was added into a mixture of compound38-a (50 mg, 0.23 mmol), HATU (266 mg, 0.46 mmol), and4-methylmorpholine (118 mg, 1.17 mmol) in DMF (2 mL). The resultingsolution was stirred at room temperature overnight. The solution waspurified by prep-HPLC with 0-80% MeCN/H₂O to afford 8.3 mg of Example 38as a white solid. [M+H]⁺401; ¹H NMR (400 MHz, Chloroform-d) δ 10.51 (s,1H), 8.80 (d, J=5.0 Hz, 2H), 8.66 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.22(s, 1H), 8.11 (d, J=7.6 Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 7.35 (d, J=5.2Hz, 2H), 5.88 (m, 1H), 2.44 (s, 3H), 1.77 (d, J=6.7 Hz, 6H).

Example 39

Step 39-1

A mixture of methyl 4-chloro-5-methylpyridine-2-carboxylate (100 mg,0.54 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole(242.6 mg, 1.08 mmol), Pd(PPh₃)₄ (124.5 mg, 0.11 mmol), and K₂CO₃ (223.4mg, 1.62 mmol) in dioxane (5 mL) was stirred at 100° C. under nitrogenatmosphere overnight. The reaction mixture was concentrated under vacuumand purified by reverse phase flash chromatograph with 0-33% MeCN/H₂O toafford compound 39-a (40 mg, 29.90%) as a yellow solid.

Step 39-2

Example 39 was prepared from compound 39-a and compound 1-c followingsimilar protocol as shown in Step 18-2. [M+H]⁺ 421; ¹H NMR (400 MHz,Chloroform-d) δ 10.49 (s, 1H), 8.61 (t, J=4.2 Hz, 2H), 8.34 (s, 1H),8.10 (d, J=7.5 Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 7.91 (s, 1H), 5.87 (m,1H), 2.84 (s, 3H), 2.60 (s, 3H), 1.76 (d, J=6.7 Hz, 6H).

Example 40

Step 40-1

A mixture of methyl5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate(100 mg, 0.36 mmol), 4-bromo-2-methyl-1,3-thiazole (128.5 mg, 0.72mmol), Pd(PPh₃)₄ (83.4 mg, 0.07 mmol), and K₂CO₃ (149.6 mg, 1.08 mmol)in dioxane (5 mL) was stirred at 100° C. under nitrogen atmosphereovernight. The reaction mixture was concentrated under reduced pressureand the residue was purified by reverse phase flash chromatography with0-36% MeCN/H₂O to afford compound 40-a (80 mg, 89.29%) as a brown oil.

Step 40-2

Example 40 was prepared from compound 40-a and compound 1-c followingsimilar protocol as shown in Step 18-2. [M+H]⁺ 421; ¹H NMR (400 MHz,Chloroform-d) δ 10.54 (s, 1H), 8.66-8.57 (m, 3H), 8.09 (d, J=7.5 Hz,1H), 8.00 (t, J=8.0 Hz, 1H), 7.48 (s, 1H), 5.89 (m, 1H), 2.83 (s, 3H),2.64 (s, 3H), 1.76 (d, J=6.6 Hz, 6H).

Example 41

Compound 41-a was prepared following the same protocol described in Step37-1. Example 41 was prepared from compound 41-a and compound 22-afollowing similar protocol described in Step 29-1. [M+H]⁺ 417. ¹H NMR(400 MHz, Chloroform-d) δ 10.55 (s, 1H), 8.76 (s, 1H), 8.72 (s, 1H),8.64 (s, 1H), 8.42 (d, J=8.3 Hz, 1H), 8.23 (s, 1H), 8.13 (d, J=7.2 Hz,1H), 8.02 (t, J=8.1 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.51 (s, 1H), 5.92(m, 1H), 4.20 (d, J=5.3 Hz, 2H), 2.46 (s, 3H), 1.75 (d, J=6.9 Hz, 3H).

Example 42

Compound 42-a was prepared following a similar protocol as shown in Step40-1. Example 42 was prepared from compound 42-a and 1-c following asimilar protocol as shown in Step 29-1. [M+H]⁺ 447. ¹H NMR (400 MHz,Chloroform-d) δ 10.49 (s, 1H), 8.69-8.60 (m, 2H), 8.33 (s, 1H), 8.11 (d,J=7.6 Hz, 1H), 8.02 (t, J=7.9 Hz, 1H), 7.88 (s, 1H), 5.87 (m, 1H), 2.60(s, 3H), 2.43 (s, 1H), 1.76 (d, J=6.7 Hz, 6H), 1.28 (d, J=8.1 Hz, 2H),1.21 (d, J=8.1 Hz, 2H).

Example 43

Example 43 was prepared from compound 42-a and 22-a following a similarprotocol as shown in Step 29-1. [M+H]⁺ 463. ¹H NMR (400 MHz,Chloroform-d) δ 10.53 (s, 1H), 8.58 (s, 1H), 8.42 (d, J=8.3 Hz, 1H),8.32 (s, 1H), 8.14 (d, J=7.6 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.85 (s,1H), 5.90 (m, 1H), 4.19 (d, J=6.0 Hz, 2H), 3.15 (s, 1H), 2.60 (s, 3H),2.41 (m, 1H), 1.74 (d, J=6.8 Hz, 3H), 1.30-1.16 (m, 4H).

Example 44

Compound 44-a was prepared following a similar protocol as shown in Step40-1. Example 44 was prepared from compound 44-a and 1-c following asimilar protocol as shown in Step 29-1. [M+H]⁺ 446. ¹H NMR (400 MHz,Chloroform-d) δ 10.52 (s, 1H), 8.62 (d, J=8.3 Hz, 1H), 8.53 (s, 1H),8.37 (s, 1H), 8.10 (m, 1H), 8.00 (t, J=7.9 Hz, 1H), 7.26 (d, J=3.7 Hz,1H), 6.87 (d, J=3.7 Hz, 1H), 5.89 (m, 1H), 2.63 (s, 3H), 2.17 (m, 1H),1.76 (d, J=6.6 Hz, 6H), 1.16-1.07 (m, 2H), 0.87-0.85 (m, 2H).

Example 45

Example 45 was prepared from compound 44-a and 22-a following a similarprotocol as shown in Step 29-1. [M+H]⁺ 462. ¹H NMR (400 MHz,Chloroform-d) δ 10.55 (s, 1H), 8.52 (s, 1H), 8.41 (d, J=8.3 Hz, 1H),8.36 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 7.26 (d,J=3.8 Hz, 1H), 6.87 (d, J=3.7 Hz, 1H), 5.92 (m, 1H), 4.19 (t, J=6.3 Hz,2H), 3.51 (s, 1H), 3.22 (t, J=6.4 Hz, 1H), 2.62 (s, 3H), 2.17 (m, 1H),1.74 (d, J=6.8 Hz, 3H), 1.16-1.07 (m, 2H), 0.87-0.85 (m, 2H).

Example 46

Step 46-1

A mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (150 mg, 0.64 mmol),1-cyclopropyl-4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(226.0 mg, 0.97 mmol), Pd(PPh₃)₄ (74.4 mg, 0.06 mmol) and K₂CO₃ (266.9mg, 1.93 mmol) in DME (5 mL) and H₂O (1 mL) was stirred at 100° C. undernitrogen atmosphere for 1 h. The mixture was allowed to cool to roomtemperature and acidified to pH 3˜4 with conc.HCl. Solvent was removedin vacuo and the residue was purified by reverse phase flashchromatography with 0-40% MeCN/H₂O to afford compound 46-a (150 mg,89.54%) as a light brown solid.

Step 46-2

A mixture of compound 46-a (50 mg, 0.19 mmol) and1-Chloro-N,N,2-trimethyl-1-propenylamine (30.8 mg, 0.23 mmol) in DCM (2mL) was stirred at room temperature for 1 h. To the above solution wasadded pyridine (45.6 mg, 0.58 mmol) and compound 1-c (58.9 mg, 0.29mmol). The resulting mixture was stirred at room temperature for 1 h.Solvent was removed under vacuum and the residue was purified by reversephase flash chromatography with 0-60% CH₃CN/H₂O to afford Example 46(12.5 mg) as a white solid. [M+H]⁺ 447; ¹H NMR (400 MHz, Chloroform-d) δ9.18 (d, J=16.6 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.14-8.08 (m, 2H), 7.99(t, J=8.0 Hz, 1H), 7.65-7.63 (m, 2H), 7.13 (d, J=13.1 Hz, 1H), 5.75 (m,1H), 3.68 (m, 1H), 2.49 (s, 3H), 1.74 (d, J=6.7 Hz, 6H), 1.19 (m, 2H),1.12 (m, 2H).

Example 47

Example 47

Step 47-1

A mixture of compound 46-a (50 mg, 190 mmol) and1-Chloro-N,N,2-trimethyl-1-propenylamine (30.8 mg, 230 mmol) in DCM (2mL) was stirred at room temperature for 1 h. Pyridine (45.6 mg, 0.58mmol) and compound 47-a (75.6 mg, 0.29 mmol) were added and theresulting mixture was stirred at room temperature for 1 h. The reactionwas quenched with MeOH (2 mL) and K₂CO₃ (53.1 mg, 0.38 mmol) was added.The resulting mixture was stirred at room temperature for 5 h. Solventwas removed in vacuo and the residue was purified by reverse phase flashchromatography with 0-60% MeCN/H₂O to afford Example 47 (9.5 mg) as awhite solid. [M+H]⁺ 463; ¹H NMR (400 MHz, Chloroform-d) δ 9.18 (d,J=16.6 Hz, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.14-8.11 (m, 2H), 8.02 (t,J=8.0 Hz, 1H), 7.65-7.60 (m, 2H), 7.13 (d, J=13.1 Hz, 1H), 5.76 (m, 1H),4.23-4.12 (m, 2H), 3.69 (m, 1H), 2.50 (s, 3H), 1.73 (d, J=6.8 Hz, 3H),1.22 (m, 2H), 1.09 (m, 2H).

Example 48

Example 48 was prepared from compound 46-a and compound 17-a followingthe same protocol as shown in Step 46-2. [M+H]+ 463; ¹H NMR (400 MHz,Chloroform-d) δ 9.15 (d, J=16.7 Hz, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.13(d, J=8.2 Hz, 1H), 8.05 (t, J=8.1 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H),7.68-7.65 (m, 1H), 7.14 (d, J=13.1 Hz, 1H), 3.90 (m, 1H), 3.68 (m, 1H),2.50 (s, 3H), 1.53 (d, J=6.9 Hz, 6H), 1.22 (m, 2H), 1.14 (m, 2H).

Example 49

Example 49 was prepared following the same protocol as described inExample 46. [M+H]⁺ 449; ¹H NMR (400 MHz, Chloroform-d) δ 9.20 (d, J=16.6Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.10 (d, J=7.6Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.13 (d,J=13.2 Hz, 1H), 5.76 (m, 1H), 4.58 (m, 1H), 2.51 (s, 3H), 1.74 (d, J=6.7Hz, 6H), 1.59 (d, J=6.7 Hz, 6H).

Example 50

Example 50 was prepared following the same protocol as described inExample 47. [M+H]⁺ 465; ¹H NMR (400 MHz, Chloroform-d) δ 9.22 (d, J=16.5Hz, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.19-8.09 (m, 2H), 8.02 (t, J=7.9 Hz,1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.14 (d, J=13.2 Hz, 1H), 5.71 (m, 1H),4.59 (m, 1H), 4.18 (m, 2H), 2.51 (s, 3H), 1.73 (d, J=6.8 Hz, 3H), 1.60(d, J=6.7 Hz, 6H).

Example 51

Example 51 was prepared following the same protocol as described inExample 48. [M+H]⁺ 449; ¹H NMR (400 MHz, Chloroform-d) δ 9.17 (d, J=16.8Hz, 1H), 8.54 (d, J=8.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.06 (t, J=8.1Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 7.14 (d,J=13.1 Hz, 1H), 4.58 (m, 1H), 3.90 (m, 1H), 2.51 (s, 3H), 1.60 (d, J=6.7Hz, 6H), 1.53 (d, J=6.9 Hz, 6H).

Example 52

Example 52 was prepared following the same protocol as described inExample 46. [M+H]⁺ 463; 1H NMR (400 MHz, Chloroform-d) δ 9.20 (d, J=16.7Hz, 1H), 8.56 (dd, J=8.3, 0.9 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.10 (d,J=8.0 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.73-7.67 (m, 2H), 7.14 (d,J=13.2 Hz, 1H), 5.77 (m, 1H), 2.52 (s, 3H), 1.75 (d, J=6.7 Hz, 6H), 1.68(s, 9H).

Example 53

Example 53 was prepared following the same protocol as described inExample 48. [M+H]⁺ 463; ¹H NMR (400 MHz, Chloroform-d) δ 9.17 (d, J=16.8Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.06 (t, J=8.1Hz, 1H), 7.74-7.69 (m, 3H), 7.14 (d, J=13.1 Hz, 1H), 3.91 (m, 1H), 2.51(s, 3H), 1.68 (s, 9H), 1.53 (d, J=6.9 Hz, 6H).

Example 54

Example 54 was prepared following the same protocol as described inExample 47. [M+H]⁺ 479; ¹H NMR (400 MHz, Chloroform-d) δ 9.20 (d, J=16.8Hz, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.16-8.11 (m, 2H), 8.02 (t, J=8.0 Hz,1H), 7.71-7.69 (m, 2H), 7.14 (d, J=13.2 Hz, 1H), 5.76 (m, 1H), 4.24-4.13(m, 2H), 2.52 (s, 3H), 1.73 (d, J=6.9 Hz, 3H), 1.66 (s, 9H).

Example 55

Step 55-1

A mixture of methyl 5-bromo-2-fluoro-4-methylbenzoate (1.7 g),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (2.3 g, 7.7mmol), Pd(dppf)Cl₂ CH₂Cl₂ (24 mg, 0.03 mmol), and KOAc (1.6 g, 19.2mmol) in dioxane (20 mL) was stirred at 85° C. overnight. Solvent wasremoved in vacuo. The residue was dissolved in EtOAc, washed withsaturated NaCl, dried with Na₂SO₄, and concentrated in vacuo.Purification of the residue on silica gel column with PE/EtOAc (10:1 to5:1) provided 1.5 g of compound 55-a (79.3%, 2 steps) as an off-whitesolid.

Step 55-2

A mixture of compound 55-a (300 mg, 1.0 mmol),4-bromo-1-(trifluoromethyl)-1H-pyrazole (258 mg, 1.2 mmol), Pd(PPh₃)₄(115 mg, 0.10 mmol) and K₂CO₃ (414 mg, 3.0 mmol) in DME (8 mL) and H₂O(2 mL) was stirred at 100° C. under nitrogen atmosphere for 1 h. Thereaction mixture was cooled to room temperature and acidified to pH 3˜4with conc.HCl. Solvent was removed in vacuo and the residue was purifiedby reverse phase flash chromatography with 0-60% CH₃CN in water toafford compound 55-b (170 mg, 57.8%) as a light brown solid.

Step 55-3

Example 55 was prepared from compound 55-b following the same protocolas described in Step 46-2. [M+H]⁺ 475; ¹H NMR (400 MHz, Chloroform-d) δ9.18 (d, J=16.5 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H),8.12 (d, J=7.6 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.80-7.97 (m, 2H), 5.75(m, 1H), 2.50 (s, 3H), 1.75 (d, J=6.6 Hz, 6H).

Example 56

Example 56 was prepared from compound 55-b and compound 17-a followingthe same protocol as described in Step 46-2. [M+H]⁺ 475; ¹H NMR (400MHz, Chloroform-d) δ 9.15 (d, J=16.6 Hz, 1H), 8.54 (d, J=8.3 Hz, 1H),8.17 (d, J=8.1 Hz, 1H), 8.07 (t, J=8.1 Hz, 1H), 7.97-7.94 (m, 2H), 7.74(d, J=7.9 Hz, 1H), 7.21 (d, J=13.0 Hz, 1H), 3.89 (m, 1H), 2.50 (s, 3H),1.54 (d, J=6.9 Hz, 6H).

Example 57

Example 57 was prepared from compound 55-b following the same protocolas described in Step 47-1. [M+1]⁺491; ¹H NMR (400 MHz, Chloroform-d) δ9.18 (d, J=16.3 Hz, 1H), 8.48 (d, J=8.3 Hz, 1H), 8.17-8.11 (m, 2H), 8.03(t, J=8.0 Hz, 1H), 7.97-7.94 (m, 2H), 7.20 (d, J=12.9 Hz, 1H), 5.74 (m,1H), 4.18 (m, 2H), 2.50 (s, 3H), 1.73 (d, J=6.8 Hz, 3H).

Example 58

Step 58-1

A mixture of compound 55-a (300 mg, 1.02 mmol),3-bromo-1-(propan-2-yl)-1H-pyrazole (267.6 mg, 1.42 mmol), Pd(PPh₃)₄(118 mg, 0.10 mmol), K₂CO₃ (422 mg, 3.00 mmol) in 1,4-dioxane (10 mL)was stirred at 100° C. overnight. Solvent was removed in vacuo and theresidue was purified by silica gel column chromatography eluting with0-50% EtOAc/PE to give 210 mg (74.6%) of compound 58-a as a white solid.

Step 58-2

Example 58 was prepared from compound 58-a following a similar protocolas described in Step 18-2. [M+H]⁺ 449. ¹H NMR (400 MHz, Chloroform-d) δ9.17 (d, J=16.2 Hz, 1H), 8.57 (d, J=8.3 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H),8.10 (d, J=7.5 Hz, 1H), 7.99 (t, J=8.0 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H),7.13 (d, J=13.2 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 5.78 (m, 1H), 4.57 (m,1H), 2.60 (s, 3H), 1.75 (d, J=6.7 Hz, 6H), 1.59 (d, J=6.7 Hz, 6H).

Example 59

Example 59 was prepared from compound 58-a and compound 17-a following asimilar protocol as described in Step 18-2. [M+H]+ 449. ¹H NMR (400 MHz,Chloroform-d) δ 9.14 (d, J=16.5 Hz, 1H), 8.56 (d, J=8.3 Hz, 1H), 8.38(d, J=8.4 Hz, 1H), 8.05 (t, J=8.0 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.51(d, J=2.3 Hz, 1H), 7.14 (d, J=13.2 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 4.58(m, 1H), 3.92 (m, 1H), 2.60 (s, 3H), 1.59 (d, J=6.8 Hz, 6H), 1.54 (d,J=6.8 Hz, 6H).

Example 60

Step 60-1

To a solution of compound 58-a (60 mg, 0.217 mmol) in MeOH (6 mL) andH₂O (2 mL) was added LiOH (52 mg, 2.17 mmol). The resulting solution wasstirred at room temperature for 2 h. Solvent was removed in vacuo andthe residue was purified by flash-Prep-HPLC with 0-100% MeCN/H₂O toafford 40 mg (70%) of compound 60-a as a white solid.

Step 60-2

Example 60 was prepared from compound 60-a following the same protocolas described in Step 47-1. [M+H]⁺ 465. ¹H NMR (400 MHz, Chloroform-d) δ9.19 (d, J=16.1 Hz, 1H), 8.50 (d, J=8.3 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H),8.12 (d, J=7.6 Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 7.51 (d, J=2.2 Hz, 1H),7.13 (d, J=13.2 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 5.77 (m, 1H), 4.58 (m,1H), 4.25-4.10 (m, 2H), 2.99 (s, 1H), 2.60 (s, 3H), 1.73 (d, J=7.0 Hz,3H), 1.59 (d, J=6.7 Hz, 6H).

Example 61

Step 61-1

A mixture of compound 55-a (300 mg, 1.02 mmol),4-bromo-1-(propan-2-yl)-1H-imidazole (230 mg, 1.22 mmol), Pd(PPh₃)₄(117.7 mg, 0.10 mmol), and K₂CO₃ (422 mg, 3.06 mmol) in 1,4-dioxane (2mL) was stirred at 100° C. overnight. Solvent was removed in vacuo andthe residue was purified on a silica gel column with 30% EtOAc in PE toafford 130 mg (46%) of compound 61-a as a yellow solid.

Step 61-2

Compound 61-a (130 mg, 0.47 mmol) was added into a mixture of sodiumhydroxide (94 mg, 2.35 mmol) in methanol (6 mL) and H₂O (2 mL). Theresulting solution was stirred at room temperature for 2 h. Solvent wasremoved in vacuo and the crude product was purified by Flash-Prep-HPLCwith the 0-100% MeCN/H₂O to afford 100 mg (81%) of compound 61-b as awhite solid.

Step 61-3

Example 61 was prepared from compound 61-b following the same protocolas described in Step 46-2. [M+H]⁺ 449; ¹H NMR (400 MHz, Chloroform-d) δ9.19 (d, J=15.6 Hz, 1H), 8.57 (d, J=8.3 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H),8.10 (d, J=7.6 Hz, 1H), 7.99 (t, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.18 (s,1H), 7.15 (d, J=4.8 Hz, 1H), 5.80 (m, 1H), 4.43 (m, 1H), 2.63 (s, 3H),1.75 (d, J=6.6 Hz, 6H), 1.59 (d, J=6.7 Hz, 6H).

Example 62

Example 62 was prepared from compound 61-b and compound 17-a following asimilar protocol as described in Step 46-2. [M+H]⁺ 449; ¹H NMR (400 MHz,Chloroform-d) δ 9.15 (d, J=15.9 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.42(d, J=8.4 Hz, 1H), 8.04 (t, J=8.1 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.67(s, 1H), 7.28 (s, 1H), 7.12 (d, J=13.2 Hz, 1H), 4.43 (m, 1H), 3.92 (m,1H), 2.62 (s, 3H), 1.59 (d, J=6.8 Hz, 2H), 1.53 (d, J=6.8 Hz, 2H).

Example 63

Example 63 was prepared from compound 61-b following the same protocolas described in Step 47-1. [M+H]⁺ 465; ¹H NMR (400 MHz, Chloroform-d) δ9.36 (d, J=13.4 Hz, 1H), 8.47 (d, J=8.3 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H),8.10 (d, J=7.6 Hz, 1H), 7.99 (t, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.17 (s,1H), 7.10 (d, J=12.8 Hz, 1H), 5.83 (m, 1H), 4.44 (m, 1H), 4.16 (m, 2H),2.59 (s, 3H), 1.72 (d, J=6.8 Hz, 3H), 1.60 (d, J=6.7 Hz, 6H).

Example 64

Step 64-1

In a sealed vial a mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (100mg, 0.43 mmol), 2-(tributylstannyl) pyridine (190 mg, 0.52 mmol),Pd(PPh₃)₄ (49 mg, 0.04 mmol) in DMF (2 mL) was heated in microwave at160° C. for 1 hour. Solvent was removed in vacuo, and the residue waspurified by Flash-Prep-HPLC with 0-100% MeCN/H₂O to afford 40 mg (37%)of compound 64-a as a yellow solid.

Step 64-2

Example 64 was prepared from compound 64-a following the same protocolas described in Step 46-2. [M+H]⁺ 418; ¹H NMR (400 MHz, Chloroform-d) δ9.19 (d, J=16.1 Hz, 1H), 8.74 (d, J=4.4 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H),8.25 (d, J=8.3 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H),7.84 (td, J=7.7, 1.8 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.34 (dd, J=7.5,5.0 Hz, 1H), 7.19 (d, J=13.1 Hz, 1H), 5.78 (m, 1H), 2.49 (s, 3H), 1.75(d, J=6.7 Hz, 6H).

Example 65

Step 65-1

A mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (100 mg, 0.40 mmol),(pyridin-3-yl)boronic acid (64 mg, 0.52 mmol), Pd(PPh₃)₄ (99 mg, 0.08mmol), and K₂CO₃ (179 mg, 1.3 mmol) in ethylene glycol dimethyl ether (4mL) and H₂O (2 mL) was stirred at 100° C. overnight.

Solvent was removed in vacuo, and the residue was purified byFlash-Prep-HPLC with 0-70% MeCN/H₂O to afford 40 mg (37%) of compound65-a as a yellow solid.

Step 65-2

Example 65 was prepared from compound 65-a following the same protocolas described in Step 46-2. [M+H]⁺ 418; ¹H NMR (400 MHz, Chloroform-d) δ9.19 (d, J=16.2 Hz, 1H), 8.69-8.64 (m, 2H), 8.55 (d, J=8.3 Hz, 1H),8.12-8.09 (m, 2H), 8.01 (t, J=8.0 Hz, 1H), 7.71 (m, 1H), 7.45 (dd,J=7.5, 5.1 Hz, 1H), 7.22 (d, J=13.0 Hz, 1H), 5.75 (m, 1H), 3.51 (s, 1H),2.39 (s, 3H), 1.75 (d, J=6.7 Hz, 6H).

Example 66

Step 66-1

A mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (100 mg, 0.43 mmol),(pyridin-4-yl)boronic acid (64 mg, 0.52 mmol), Pd(PPh₃)₄ (99 mg, 0.08mmol), and K₂CO₃ (179 mg, 1.3 mmol) in ethylene glycol dimethyl ether (4mL), and H₂O (2 mL) was stirred at 100° C. overnight. Solvent wasremoved in vacuo and the crude product was purified by Flash-Prep-HPLCwith 0-100% MeCN/H₂O to afford 70 mg (75%) of compound 66-a as a whitesolid.

Step 66-2

Example 66 was prepared from compound 66-a following the same protocolas described in Step 46-2. [M+H]⁺ 418; ¹H NMR (400 MHz, Chloroform-d) δ9.18 (d, J=16.2 Hz, 1H), 8.75 (s, 2H), 8.55 (d, J=8.3 Hz, 1H), 8.14-8.09(m, 2H), 8.01 (t, J=7.9 Hz, 1H), 7.35 (d, J=5.0 Hz, 2H), 7.23 (d, J=13.0Hz, 1H), 5.75 (m, 1H), 2.40 (s, 3H), 1.75 (d, J=6.7 Hz, 6H).

Example 67

Step 67-1

A mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (100 mg, 0.43 mmol),2-methyl-5-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole(193.2 mg, 0.86 mmol), Pd(PPh₃)₄ (99.2 mg, 0.09 mmol), and K₂CO₃ (177.9mg, 1.29 mmol) in ethylene glycol dimethyl ether (5 mL) and H₂O (1 mL)was stirred at 100° C. under nitrogen atmosphere overnight. The mixturewas allowed to cool down to room temperature, and acidified to pH 3˜4with 1N HCl. Solvent was removed in vacuo and the residue was purifiedby reverse phase chromatography with 0-38% MeCN/H₂O═38:62) to affordcompound 67-a (40 mg, 37.10%) as a yellow solid.

Step 67-2

Example 67 was prepared from compound 67-a following the same protocolas described in Step 46-2. [M+H]⁺ 438; ¹H NMR (400 MHz, Chloroform-d) δ9.15 (d, J=16.1 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.20 (d, J=8.1 Hz, 1H),8.11 (d, J=7.6 Hz, 1H), 8.00 (t, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.18 (d,J=12.9 Hz, 1H), 5.75 (m, 1H), 2.79 (s, 3H), 2.49 (s, 3H), 1.74 (d, J=6.7Hz, 6H).

Example 68

Step 68-1

A mixture of methyl2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(100 mg, 0.34 mmol), 4-bromo-2-methyl-1,3-thiazole (72 mg, 0.40 mmol),Pd(PPh₃)₄ (30 mg, 0.03 mmol), K₂CO₃ (141 mg, 1.02 mmol) in ethyleneglycol dimethyl ether (5 mL) and H₂O (1 mL) was stirred at 100° C.overnight. Solvent was removed in vacuo, and the residue was purified byFlash-Prep-HPLC with 0-80% MeCN/H₂O to afford 55 mg (65%) of compound68-a as a yellow solid.

Step 68-2

Example 68 was prepared from compound 68-a following the same protocolas described in Step 46-2. [M+H]⁺ 438; ¹H NMR (400 MHz, Chloroform-d) δ9.17 (d, J=16.1 Hz, 1H), 8.56 (d, J=8.3 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H),8.10 (d, J=7.6 Hz, 1H), 8.00 (t, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (d,J=13.2 Hz, 1H), 5.77 (m, 1H), 2.81 (s, 3H), 2.54 (s, 3H), 1.75 (d, J=6.8Hz, 6H).

Example 69

Example 69 was prepared following a similar protocol as described inExample 61. [M+H]⁺ 463.

¹H NMR (400 MHz, Chloroform-d) δ 9.15 (d, J=16.1 Hz, 1H), 8.55 (d, J=8.3Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.99 (t, J=8.0Hz, 1H), 7.13 (d, J=13.1 Hz, 1H), 6.90 (d, J=3.5 Hz, 1H), 6.79 (d, J=3.6Hz, 1H), 5.77 (m, 1H), 2.52 (s, 3H), 2.13 (m, J=8.7, 5.0 Hz, 1H), 1.74(d, J=6.7 Hz, 6H), 1.15 (m, 2H), 0.80 (m, 2H).

Example 70

Example 70 was prepared following a similar protocol as described inExample 63. [M+H]⁺ 479. ¹H NMR (400 MHz, Chloroform-d) δ 9.13 (d, J=16.3Hz, 1H), 8.48 (d, J=8.3 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.12 (d, J=7.6Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 7.13 (d, J=13.1 Hz, 1H), 6.90 (d, J=3.6Hz, 1H), 6.79 (d, J=3.6 Hz, 1H), 5.75 (m, 1H), 4.17 (m, J=11.9, 5.9 Hz,2H), 2.52 (s, 3H), 2.15 (m, 1H), 1.73 (d, J=6.8 Hz, 3H), 1.05 (m, 2H),0.80 (m, 2H).

Example 71

Step 71-1

A solution of 5-bromo-4-fluoro-2-methylbenzoic acid (900 mg, 3.9 mmol),methoxy(methyl)amine hydrochloride (573 mg, 5.9 mmol), HATU (2.3 g, 6.0mmol), and DIPEA (2 g, 15.5 mmol) in DCM (20 mL) was stirred at roomtemperature overnight. Then the resulting solution was diluted with sat.NaCl and extracted with EtOAc (30 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with PE/EtOAc (2:1) to give5-bromo-4-fluoro-N-methoxy-N,2-dimethylbenzamide (900 mg, 84.4%) as alight yellow oil.

Step 71-2

In a 3-necked round-bottom flask a solution of5-bromo-4-fluoro-N-methoxy-N,2-dimethylbenzamide (900 mg, 3.3 mmol) inTHF was cooled to −30° C. under nitrogen atmosphere. CH₃MgCl in THF (3M)(14.6 mL, 43.8 mmol) was added dropwise over 10 min while maintainingthe temperature below 0° C. The reaction solution was stirred at 0° C.for 0.5 h, quenched with sat. NH₄C₁ at 0° C., and extracted with EtOAc(30 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography withPE/EtOAc (2:1) to give 1-(5-bromo-4-fluoro-2-methylphenyl)ethan-1-one(600 mg, 79.6%) as a light yellow solid.

Step 71-3

A mixture of 1-(5-bromo-4-fluoro-2-methylphenyl)ethan-1-one (600 mg, 2.6mmol), 1-cyclopropane-carbonyl-1H-1,2,3-benzotriazole (885 mg, 4.8mmol), magnesium bromide ethyl etherate (4.9 g, 19.2 mmol) and DIPEA(1.2 g, 9.3 mmol) in DCM (mL) was stirred at room temperature for 3days. The resulting mixture was diluted with sat. NaCl (10 mL) and thenextracted with EtOAc (10 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by reverse flashchromatography with the following conditions (column, C18 silica gel;mobile phase, ACN in FA (0.1%) water, 0% to 100% gradient in 25 min;detector, UV 254 nm) to give1-(5-bromo-4-fluoro-2-methylphenyl)-3-cyclopropyl propane-1,3-dione (400mg, 51.4%) as a yellow oil.

Step 71-4

A solution of1-(5-bromo-4-fluoro-2-methylphenyl)-3-cyclopropylpropane-1,3-dione (400mg, 1.3 mmol) and hydroxylamine hydrochloride (318 mg, 4.6 mmol) in MeOH(10 mL) was stirred at 45° C. overnight. The resulting solution wasdiluted with sat. NaCl (20 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by reverse flash chromatography with the followingconditions (column, C18 silica gel; mobile phase, ACN in water, 0 to100% gradient in 25 min; detector, UV 254 nm) to give3-(5-bromo-4-fluoro-2-methylphenyl)-5-cyclopropyl-1,2-oxazole (170 mg,42.9%) as a yellow oil.

Step 71-5

A mixture of3-(5-bromo-4-fluoro-2-methylphenyl)-5-cyclopropyl-1,2-oxazole (170 mg,0.5 mmol), Pd(dppf)Cl₂ CH₂Cl₂ (258 mg, 0.3 mmol), and TEA (478 mg, 4.8mmol) in DMF/MeOH (4/1 mL) was stirred at 75° C. under CO atmosphereovernight. The resulting mixture was diluted with sat. NaCl and thenextracted with EtOAc (10 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by reverse flashchromatography with the following conditions (column, C18 silica gel;mobile phase, ACN in water, 0 to 80% gradient in 20 min; detector, UV254 nm) to give methyl5-(5-cyclopropyl-1,2-oxazol-3-yl)-2-fluoro-4-methylbenzoate (80 mg,50.6%) as a yellow oil.

Step 71-6

A mixture of methyl5-(5-cyclopropyl-1,2-oxazol-3-yl)-2-fluoro-4-methylbenzoate (80 mg, 0.3mmol) and LiOH (24 mg, 0.9 mmol) in THF/H₂O (1/0.3 mL) was stirred atroom temperature for 2 hours. Then the mixture was acidified to pH 4˜5with 1M HCl (aq.) and extracted with EtOAc (10 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give5-(5-cyclopropyl-1,2-oxazol-3-yl)-2-fluoro-4-methylbenzoic acid (50 mg,65.8%) as a yellow oil.

Step 71-7

To a stirred solution of5-(5-cyclopropyl-1,2-oxazol-3-yl)-2-fluoro-4-methylbenzoic acid (50 mg,0.2 mmol) in DCM (1 mL) was added(1-chloro-2-methylprop-1-en-1-yl)dimethylamine (33 mg, 0.2 mmol)dropwise at room temperature under nitrogen atmosphere. After stirringfor 1 hour, a solution of pyridine (48 mg, 0.6 mmol) and6-(1-isopropyl-1H-tetrazol-5-yl)pyridin-2-amine (86 mg, 0.4 mmol) in DCM(1 mL) was added. After stirring for another 1 hour, the solution wasquenched with water (10 mL) and then extracted with EtOAc (10 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by reverseflash chromatography with the following conditions (column, C18 silicagel; mobile phase, ACN in water, 0% to 90% gradient in 20 min; detector,UV 254 nm) to give 14 mg of Example 71 as an off-white solid. MS m/z:[M+H]⁺=448.20, t=1.928 min. ¹H NMR (400 MHz, Chloroform-d) δ 9.13 (d,J=15.8 Hz, 1H), 8.55 (d, J=8.3 Hz, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.12 (d,J=7.6 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.20 (d, J=12.9 Hz, 1H), 6.20 (s,1H), 5.75 (m, 1H), 2.62 (s, 3H), 2.10 (m, 1H), 1.74 (d, J=6.7 Hz, 6H),1.18-1.08 (m, 2H), 0.97-0.89 (m, 2H).

Example 72-A and 72-B

Step 72-1

A mixture of ethyl 2-chloro-5-fluoropyridine-4-carboxylate (1.0 g, 4.91mmol) and LiOH (1.5 g, 6.26 mmol) in THF/H₂O (20/5 mL) was stirred atroom temperature for 2 hours. The mixture was acidified with HCl (aq.),and extracted with EtOAc (30 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄.

After filtration, the filtrate was concentrated under reduced pressureto give 760 mg (88.4%) of 2-chloro-5-methylisonicotinic acid as anoff-white solid.

Step 72-2

2-Chloro-N-methoxy-N,5-dimethylisonicotinamide was prepared as describedin Step 71-1. 700 mg (73.6%) was obtained as an off-white solid.

Step 72-3

1-(2-Chloro-5-methylpyridin-4-yl)ethan-1-one was prepared as describedin Step 71-2. 400 mg (84.4%) was obtained as a light yellow oil.

Step 72-4

1-(2-Chloro-5-methylpyridin-4-yl)-3-cyclopropylpropane-1,3-dione wasprepared as described in Step 71-3. 220 mg (41.3%) was obtained as awhite solid.

Step 72-5

A mixture of 3-(2-Chloro-5-methylpyridin-4-yl)-5-cyclopropylisoxazoleand 5-(2-chloro-5-methylpyridin-4-yl)-3-cyclopropylisoxazole (190 mg,96.2%) were prepared as described in Step 71-4 as a light yellow solid.

Step 72-6

Methyl 4-(5-cyclopropylisoxazol-3-yl)-5-methylpicolinate (20 mg) andmethyl 4-(3-cyclopropylisoxazol-5-yl)-5-methylpicolinate (18 mg) wereprepared as described in Step 71-5 as a light yellow solid.

Step 72-7

Example 72-A was prepared as described in Step 29-1. 10 mg was obtainedas a dark yellow solid. MS m/z: [M+H]⁺=431.20; ¹H NMR (400 MHz,Chloroform-d) δ 10.50 (s, 1H), 8.66 (s, 1H), 8.61 (d, J=8.3 Hz, 1H),8.42 (s, 1H), 8.11 (d, J=7.5 Hz, 1H), 8.01 (t, J=8.0 Hz, 1H), 6.33 (s,1H), 5.88 (m, 1H), 2.68 (s, 3H), 2.18 (m, 1H), 1.76 (d, J=6.7 Hz, 6H),1.20-1.17 (m, 2H), 1.13-1.10 (m, 2H).

Example 72-B was prepared as described in Sep 29-1. 4.8 mg was obtainedas a off-white solid. MS m/z: [M+H]⁺=431.20. ¹H NMR (400 MHz,Chloroform-d) δ 10.46 (s, 1H), 8.68-8.59 (m, 2H), 8.57 (s, 1H), 8.11 (d,J=7.5 Hz, 1H), 8.02 (t, J=8.0 Hz, 1H), 6.46 (s, 1H), 5.86 (m, 1H), 2.69(s, 3H), 2.12 (m, 1H), 1.76 (d, J=6.7 Hz, 6H), 1.21-1.13 (m, 2H),1.01-0.92 (m, 2H).

Example 73

Step 73-1

A mixture of 1-methylpyrazol-4-ylboronic acid (113 mg, 0.89 mmol),5-bromo-2-methoxy-4-methyl benzoic acid (200 mg, 0.82 mmol), Pd(PPh₃)₄(94 mg, 0.08 mmol), and K₂CO₃ (451 mg, 3.26 mmol) in DME/H₂O (5/1 mL)was stirred at 100° C. under nitrogen atmosphere overnight. The solutionwas diluted with H₂O (10 mL), acidified to pH 4˜5 with 1 M HCl (aq.),and extracted with EtOAc (10 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby silica gel column chromatography with DCM/MeOH (30:1) to give2-methoxy-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid (140 mg,Y=69.9%) as a yellow oil.

Step 73-2.

Example 73 was prepared as described in Step 71-7. 12 mg was obtained asan off-white solid. MS m/z: [M+H]⁺=433.20. ¹H NMR (400 MHz, DMSO-d6) δ10.73 (s, 1H), 8.45 (m, 1H), 8.14 (t, J=8.0 Hz, 1H), 8.01-7.94 (m, 2H),7.87 (s, 1H), 7.67 (s, 1H), 7.22 (s, 1H), 5.85 (m, 1H), 4.01 (s, 3H),3.90 (s, 3H), 2.46 (s, 3H), 1.63 (d, J=6.6 Hz, 6H).

Example 74

Example 74 was prepared as described in Step 71-7. 12 mg was obtained asan off-white solid. MS m/z 432.20, 433.20 [M+H]+; ¹H NMR (400 MHz,DMSO-d6) δ 10.69 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.21 (t, J=8.1 Hz,1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.66 (s, 1H),7.20 (s, 1H), 3.99 (s, 3H), 3.89-3.80 (m, 4H), 2.45 (s, 3H), 1.40 (d,J=6.9 Hz, 6H).

Example 75

Step 75-1

A solution of 5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-fluoro-4-methylbenzoicacid (300 mg, 1.2 mmol) and sodium methylate (15 mL, 30%) was stirred at80° C. overnight. The solution was quenched with water, acidified to pH4˜5 with 1M HCl (aq.), and extracted with EtOAc (10 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography with DCM/MeOH (30:1) to give5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxy-4-methylbenzoic acid (310mg, 98.77%) as a light pink solid.

Step 75-2

Example 75 was prepared as described in Step 71-7. 15.3 mg was obtainedas an off-white solid. MS m/z: [M+H]⁺=459.40. ¹H NMR (400 MHz,Chloroform-d) δ 10.55 (s, 1H), 8.61 (dd, J=8.3, 1.1 Hz, 1H), 8.25 (s,1H), 8.04 (dd, J=7.6, 1.1 Hz, 1H), 7.97 (t, J=7.9 Hz, 1H), 7.65 (d,J=12.6 Hz, 2H), 6.96 (s, 1H), 5.81 (m, 1H), 4.11 (s, 3H), 3.68 (m, 1H),2.51 (s, 3H), 1.77 (d, J=6.7 Hz, 6H), 1.24-1.21 (m, 2H), 1.18-1.05 (m,2H).

Example 76

Example 76 was prepared as described in Step 71-7. 12.6 mg was obtainedas an off-white solid. MS m/z: [M+H]⁺=459.25. ¹H NMR (400 MHz,Chloroform-d) δ 10.55 (s, 1H), 8.58 (dd, J=8.3, 0.7 Hz, 1H), 8.24 (s,1H), 8.02 (t, J=8.1 Hz, 1H), 7.69-7.60 (m, 3H), 6.96 (s, 1H), 4.10 (s,3H), 3.92 (m, 1H), 3.68 (m, 1H), 2.51 (s, 3H), 1.57 (d, J=6.9 Hz, 6H),1.25-1.13 (m, 2H), 1.17-1.04 (m, 2H).

Example 77

To a stirred solution of5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxy-4-methylbenzoic acid (50 mg,0.2 mmol) in DCM (1 mL) was added(1-chloro-2-methylprop-1-en-1-yl)dimethylamine (30 mg, 0.2 mmol)dropwise at room temperature under nitrogen atmosphere. After 2 hours asolution of6-[1-[(2R)-1-[(tert-butyldimethylsilyl)oxy]propan-2-yl]-1H-1,2,3,4-tetrazol-5-yl]pyridin-2-amine(93 mg, 0.3 mmol) and pyridine (44 mg, 0.6 mmol) in DCM (1 mL) wasadded. The reaction was stirred for 2 hours and conc HCl (0.4 mL) wasadded dropwise at room temperature. After 1 hour, the resulting mixturewas concentrated under reduced pressure. The residue was purified byreverse flash chromatography with the following conditions (column, C18silica gel; mobile phase, ACN in water, 0 to 100% gradient in 25 min;detector, UV 254 nm) to give5-(1-cyclopropyl-1H-pyrazol-4-yl)-N-(6-[1-[(2R)-1-hydroxypropan-2-yl]-1H-1,2,3,4-tetrazol-5-yl]pyridin-2-yl)-2-methoxy-4-methylbenzamide(13 mg, 14.8%) as an off-white solid. MS m/z: [M+H]⁺=475.25. ¹H NMR (400MHz, Chloroform-d) δ 10.65 (s, 1H), 8.57 (dd, J=7.1, 2.2 Hz, 1H), 8.23(s, 1H), 8.04-7.94 (m, 2H), 7.66-7.59 (m, 2H), 6.95 (s, 1H), 5.68 (m,1H), 4.16 (d, J=6.4 Hz, 2H), 4.14 (s, 3H), 3.93 (s, 1H), 3.67 (m, 1H),2.50 (s, 3H), 1.74 (d, J=6.9 Hz, 3H), 1.22-1.19 (m, 2H), 1.17-1.02 (m,2H).

Example 78

Step 78-1

A mixture of methyl2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(400 mg, 1.4 mmol), 3-bromo-1-(propan-2-yl)-1H-pyrazole (312 mg, 1.8mmol), K₂CO₃ (560 mg, 4.1 mmol), and Pd(PPh₃)₄ (80 mg, 0.1 mmol) inDME/H₂O (/5/1 mL) was stirred at 100° C. under nitrogen atmosphere for 1hour. The resulting mixture was cooled to room temperature, diluted withwater (20 mL), and extracted with EtOAc (20 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith PE/EtOAc (20:1) to give methyl2-fluoro-4-methyl-5-[1-(propan-2-yl)-1H-pyrazol-3-yl] benzoate (173 mg,46%) as a yellow oil.

Step 78-2

To a stirred solution of methyl2-fluoro-4-methyl-5-[1-(propan-2-yl)-1H-pyrazol-3-yl]benzoate (173 mg,0.6 mmol) in THF/H₂O (3/1 mL) was added LiOH (200 mg, 8.4 mmol) and theresulting mixture was stirred at room temperature overnight. Then themixture was acidified to pH 4˜5 with 1M HCl (aq), and extracted withEtOAc (10 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give2-fluoro-5-(1-isopropylpyrazol-3-yl)-4-methylbenzoic acid (160 mg) as agrey solid.

Step 78-3

A mixture of 2-fluoro-5-(1-isopropylpyrazol-3-yl)-4-methylbenzoic acid(160 mg, 0.6 mmol) and 30% sodium methoxide in methanol (12 mL) wasstirred at 80° C. overnight. The mixture was acidified to pH 4˜5 with 1MHCl (aq) and extracted with EtOAc (10 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith DCM/MeOH (20:1) to give5-(1-isopropylpyrazol-3-yl)-2-methoxy-4-methylbenzoic acid (162 mg,96.8%) as a grey solid.

Step 78-4

Example 78 was prepared as described in Step 71-7. MS m/z:[M+H]+=461.35. ¹H NMR (400 MHz, Chloroform-d) δ 10.54 (s, 1H), 8.62 (d,J=8.3 Hz, 1H), 8.49 (s, 1H), 8.03 (d, J=7.4 Hz, 1H), 7.96 (t, J=7.9 Hz,1H), 7.49 (d, J=2.3 Hz, 1H), 6.96 (s, 1H), 6.45 (d, J=2.2 Hz, 1H), 5.83(m, 1H), 4.57 (m, 1H), 4.11 (s, 3H), 2.62 (s, 3H), 1.78 (d, J=6.7 Hz,6H), 1.59 (d, J=6.7 Hz, 6H).

Example 79

Example 79 was prepared as described in Step 71-7. MS m/z:[M+H]⁺=461.25. ¹H NMR (400 MHz, Chloroform-d) δ 10.53 (s, 1H), 8.60 (d,J=8.3 Hz, 1H), 8.48 (s, 1H), 8.01 (t, J=8.1 Hz, 1H), 7.65 (d, J=7.7 Hz,1H), 7.49 (d, J=2.2 Hz, 1H), 6.95 (s, 1H), 6.44 (d, J=2.2 Hz, 1H), 4.57(m, 1H), 4.10 (s, 3H), 3.93 (m, 1H), 2.62 (s, 3H), 1.59-1.56 (m, 12H).

Example 80

Example 80 was prepared as a white solid employing a similar procedureas shown in Example 77. MS m/z: [M+H]⁺=477.25. ¹H NMR (400 MHz,Chloroform-d) δ 10.64 (s, 1H), 8.59 (d, J=7.8 Hz, 1H), 8.47 (s, 1H),8.02-7.93 (m, 2H), 7.49 (d, J=2.2 Hz, 1H), 6.94 (s, 1H), 6.44 (d, J=2.2Hz, 1H), 5.70 (m, 1H), 4.58 (m, 1H), 4.17-4.14 (m, 5H), 2.61 (s, 3H),1.75 (d, J=6.8 Hz, 3H), 1.59 (d, J=6.6 Hz, 6H).

Example 81

Example 81 was prepared following the chemistry shown in the abovesynthetic scheme. [M+H]⁺ 475.2. ¹H NMR (400 MHz, Chloroform-d) δ 9.19(d, J=16.9 Hz, 1H), 8.56 (d, J=8.1 Hz, 1H), 8.15 (d, J=3.7 Hz, 1H), 8.13(d, J=5.0 Hz, 1H), 8.02 (dd, J=8.0, 8.0 Hz, 1H), 7.65 (s, 1H), 7.64 (s,1H), 7.14 (d, J=13.3 Hz, 1H), 6.09 (ddt, J=9.6, 6.6, 3.3 Hz, 1H),4.40-4.34 (m, 2H), 4.22 (dd, J=9.9, 3.6 Hz, 1H), 4.20-4.13 (m, 1H),3.72-3.66 (m, 1H), 2.83-2.76 (m, 1H), 2.68-2.54 (m, 1H), 2.50 (s, 3H),1.25-1.18 (m, 2H), 1.16-1.05 (m, 2H).

Example 82

Example 82 was prepared following the chemistry shown in the abovesynthetic scheme. [M+H]⁺ 475.2. ¹H NMR (400 MHz, Chloroform-d) δ 9.18(d, J=16.9 Hz, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.14 (d, J=3.7 Hz, 1H), 8.12(d, J=5.0 Hz, 1H), 8.01 (dd, J=8.0, 8.0 Hz, 1H), 7.65 (s, 1H), 7.64 (s,1H), 7.14 (d, J=13.3 Hz, 1H), 6.09 (ddt, J=9.6, 6.6, 3.3 Hz, 1H),4.40-4.34 (m, 2H), 4.22 (dd, J=9.9, 3.6 Hz, 1H), 4.20-4.13 (m, 1H),3.72-3.66 (m, 1H), 2.83-2.76 (m, 1H), 2.68-2.54 (m, 1H), 2.50 (s, 3H),1.25-1.18 (m, 2H), 1.16-1.05 (m, 2H).

Example 83

Example 83 was prepared following the chemistry shown in the abovesynthetic scheme. [M+H]⁺ 489.2. ¹H NMR (400 MHz, Chloroform-d) δ 9.26(d, J=16.4 Hz, 1H), 8.51 (d, J=8.3 Hz, 1H), 8.17-8.08 (m, 2H), 8.03 (dd,J=8.0, 8.0 Hz, 1H), 7.65 (s, 1H), 7.63 (s, 1H), 7.14 (d, J=13.1 Hz, 1H),5.59 (td, J=7.8, 5.4 Hz, 1H), 4.71 (q, J=6.2 Hz, 1H), 3.77-3.69 (m, 1H),2.50 (s, 3H), 2.48-2.40 (m, 2H), 2.38-2.30 (m, 1H), 2.19-1.97 (m, 2H),1.96-1.80 (m, 1H), 1.27-1.17 (m, 2H), 1.15-1.06 (m, 2H).

Example 84

Example 84 was prepared following the chemistry shown in the abovesynthetic scheme. [M+H]⁺ 489.2. ¹H NMR (400 MHz, Chloroform-d) δ 9.17(d, J=17.4 Hz, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H),8.12-8.08 (m, 1H), 8.03 (dd, J=8.0, 8.0 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H),7.63 (s, 1H), 7.14 (d, J=13.2 Hz, 1H), 5.64-5.49 (m, 1H), 4.64 (q, J=5.9Hz, 1H), 3.73-3.69 (m, 1H), 2.67-2.57 (m, 1H), 2.50 (s, 2H), 2.40-2.34(m, 1H), 2.32-2.26 (m, 1H), 2.22-2.11 (m, 1H), 2.10-1.96 (m, 1H),1.90-1.78 (m, 1H), 1.26-1.18 (m, 2H), 1.14-1.06 (m, 2H).

Assays

The ability (IC₅₀) of compounds to inhibit ASK1 kinase activity wasdetermined by HTRF® KinEASE™ Assay System. ASK1 was purchased fromThermofisher (Catalogue #PV4011), ATP was purchased from Sigma(Catalogue #A7699), HTRF® KinEASE™ Assay System was obtained from Cisbio(Bedford, Mass.). ½ Area plate was purchased from Perkin Elmer(Catalogue ##6005560). HTRF® KinEASE™-STK is a generic method formeasuring serine/threonine kinase activities using a time-resolvedfluorescence resonance energy transfer (TR-FRET) immunoassay. The IC₅₀value for each compound was determined in the presence of compound(various concentration from 0 to 10 μM) and a fixed amount of ATP andpeptide substrates. The test compound, 1 uM STK3 peptide substrate, and5 nM of ASK1 kinase are incubated with kinase reaction buffer containing50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, and 1 mM EGTA for 30minutes. 100 uM ATP is added to start kinase reaction and incubated for3 hours. The STK3-antibody labeled with Eu³⁺-Cryptate and 125 nMstreptavidin-XL665 are mixed in a single addition with stop reagentsprovided by the Cisbio kit used to stop the kinase reaction.Fluorescence is detected using an Envision Multilabeled 2014 reader fromPerkinElmer. The Fluorescence is measured at 615 nm (Cryptate) and 665nm (XL665) and a ratio of 665 nm/615 nm is calculated for each well. Theresulting TR-FRET is proportional to the phosphorylation level.Staurosporine was used as the positive control. IC₅₀ was determined byXLfit 5.3. By using above method, the inhibition of ASK1 was tested forthe compound of formula (I). IC₅₀ ranges are as follows: A<1 nM; 1nM<B<10 nM; 10 nM<C<100 nM; 100 nM<D<1 μM; E>1 μM.

TABLE 1 Example IC₅₀ Example IC₅₀ Example  IC₅₀ 1 C 2 C  3 C 4 C 5 C  6B 7 B 8 C  9 B 10 B 11 C 12 B 13 B 14 C 15 C 16 B 17 C 18 B 19 B 20 B 21C 22 B 23 C 24 E 25 B 26 B 27 B 28 B 29 B 30 C 31 E 32 B 33 C 34 E 35 B36 C 37 B 38 C 39 B 40 C 41 B 42 B 43 B 44 C 45 B 46 B 47 B 48 B 49 B 50B 51 B 52 B 53 B 54 B 55 C 56 D 57 B 58 C 59 E 60 C 61 C 62 E 63 C 64 D65 B 66 C 67 C 68 D 69 C 70 B 71 C 72-A/B C 73 B 74 B 75 A 76 A 77 A 78B 79 C 80 A 81 B 82 B 83 B 84 B

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

We claim:
 1. A compound represented by Formula I or a pharmaceuticallyacceptable salt or ester thereof:

wherein

is selected from the groups below

is

is

R¹ is selected from the group consisting of: 1) Hydrogen; 2) Optionallysubstituted —C₁-C₈ alkyl; 3) Optionally substituted —C₂-C₈ alkenyl; 4)Optionally substituted —C₂-C₈ alkynyl; 5) Optionally substituted —C₃-C₈cycloalkyl; 6) Optionally substituted aryl; 7) Optionally substitutedarylalkyl; 8) Optionally substituted 3- to 8-membered heterocycloalkyl;9) Optionally substituted heteroaryl; and 10) Optionally substitutedheteroarylalkyl; R² is

X is N or C—R³; R³ is selected from the group consisting of: 1)Hydrogen; 2) Halogen; 3) Optionally substituted —C₁-C₈ alkyl; and 4)Optionally substituted —C₁-C₈ alkoxyl; R⁴ is selected from the groupconsisting of: 1) Hydrogen; 2) Halogen; 3) Optionally substituted —C₁-C₈alkyl; 4) Optionally substituted —C₂-C₈ alkenyl; 5) Optionallysubstituted —C₂-C₈ alkynyl; 6) Optionally substituted —C₃-C₈ cycloalkyl;7) Optionally substituted aryl; 8) Optionally substituted arylalkyl; 9)Optionally substituted 3- to 8-membered heterocycloalkyl; 10) Optionallysubstituted heteroaryl; 11) Optionally substituted heteroarylalkyl; and12) —N(R⁵)(R⁶); wherein R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, —C₁-C₈ alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the —C₁-C₈ alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with 1-3 substituents independently selected from halo,alkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—,heteroarylC(O)NH—, —CN, alkoxy, —CF₃, aryl, and heteroaryl;alternatively, R⁵ and R⁶ are taken together with the nitrogen atom towhich they are attached to form an optionally substituted heterocyclic.2. The compound of claim 1, represented by one of Formulas (II-a),(II-c), (II-e), and (II-g), or a pharmaceutically acceptable saltthereof:

wherein

R² and R⁴ are as defined in claim
 1. 3. The compound of claim 1,represented by one of Formulas (III-a) ˜(III-n), or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R² and R⁴ are as defined in claim
 1. 4. The compound ofclaim 1, represented by one of Formulas (IV-a) ˜(IV-n), or apharmaceutically acceptable salt thereof:

wherein R¹, R² and R⁴ are as defined in claim
 1. 5. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 6. The compound of claim 1, selectedfrom the compounds set forth below or a pharmaceutically acceptable saltthereof: Com- Com- pound Structure pound Structure 13

16

22

25

28

29

32

35

41

43

45

47

50

54

57

60

63

70

77

80